Myocardial Extracellular Matrix Remodeling Research Articles

BIOMARKERS OF CARDIOVASCULAR COMPLICATIONS ASSOCIATED WITH COVID-19 DISEASE

The coronavirus disease (COVID-19), which caused a global pandemic in the world, is now becoming an endemic, seasonal disease. Therefore, the search for new biomarkers to predict the course of the disease and its outcomes remains extremely important. It has been found that COVID-19 affects not only the respiratory system but also other organs and systems of the body. In particular, the target of the SARS-CoV-2 virus is the cardiovascular system. Because the severity of COVID-19 disease is highly variable, laboratory biomarkers can provide important prognostic information already at the emergency stage, especially in patients with atypical manifestations. It has been demonstrated that viral infections, and in particular COVID-19, can cause changes in the host's lipid profile. Changes in the processes of intracellular cholesterol biosynthesis and its transport in the bloodstream of patients with COVID-19 have been reported. Thus, in patients suffering from COVID-19, significantly reduced levels of total іукгь cholesterol (C), HDL, and LDL cholesterol, and an increased ratio of triglycerides/C have been recorded. Patients with COVID-19 are characterized by an increased content of residual (remnant) cholesterol, which is defined as cholesterol present in residual lipoproteins rich in triglycerides and, as shown by the results of genetic, observational, and clinical studies, is associated with the development of atherosclerosis and overall mortality. Several peptide cardiac biomarkers have become other predictors of cardiovascular prognosis in patients with COVID-19: highly sensitive cardiac troponin – successfully used in clinical practice as a marker of myocyte damage for diagnosis and prognostic assessment of acute coronary syndrome; N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of myocardial stretch; peptide ST2 – a marker of remodeling of myocardial extracellular matrix, which prevents fibrosis, cardiac hypertrophy and apoptosis; copeptin is a biomarker of neurohumoral activation. The review provides a concise analysis of currently known cardiac biomarkers in COVID-19 and their prognostic significance.

Natriuretic Peptide Levels and Stages of Left Ventricular Dysfunction in Heart Failure with Preserved Ejection Fraction.

In heart failure with preserved ejection fraction (HFpEF), natriuretic peptide (NP) levels are frequently lower. In several trials, the outcome differed between patients with low and high NP levels. This suggests that NP could be used to identify distinct stages of left ventricular (LV) remodeling and myocardial tissue composition. This study investigated cardiac remodeling/dysfunction and myocardial tissue characteristics assessed by echocardiography and cardiac magnetic resonance (CMR) in HFpEF patients in relation to NP levels. Clinical and echocardiographic data of 152 HFpEF patients were derived from outpatient visits. A total of 71 HFpEF patients underwent CMR-derived T1-mapping. Multivariable regression analyses were performed to examine the association of NT-proBNP categories (</> median) and NT-proBNP as continuous variable with echocardiography and CMR-derived T1-mapping. Mean age was 71 ± 9, 93% of patients were women and median NT-proBNP was 195 pg/mL, with 35% of patients below the diagnostic cut-off value (<125 pg/mL). Patients with high NT-proBNP had comparable LV systolic function and LV relaxation but significantly worse LV stiffness and left atrial function compared with patients with low NT-proBNP. Higher NT-proBNP was significantly associated with higher LV stiffness and extracellular volume fraction (ECV) (β = 1.82, 95% CI: 0.19;3.44, p = 0.029). Higher NT-proBNP levels identify HFpEF patients with worse LV stiffness because of more severe myocardial extracellular matrix remodeling, representing an advanced stage of HFpEF.

Hypothalamic Oxytocin Neuron Activation Attenuates Intermittent Hypoxia-Induced Hypertension and Cardiac Dysfunction in an Animal Model of Sleep Apnea.

Obstructive sleep apnea is a prevalent and poorly treated cardiovascular disease that leads to hypertension and autonomic imbalance. Recent studies that restore cardiac parasympathetic tone using selective activation of hypothalamic oxytocin neurons have shown beneficial cardiovascular outcomes in animal models of cardiovascular disease. This study aimed to determine if chemogenetic activation of hypothalamic oxytocin neurons in animals with existing obstructive sleep apnea-induced hypertension would reverse or blunt the progression of autonomic and cardiovascular dysfunction. Two groups of rats were exposed to chronic intermittent hypoxia (CIH), a model of obstructive sleep apnea, for 4 weeks to induce hypertension. During an additional 4 weeks of exposure to CIH, 1 group was treated with selective activation of hypothalamic oxytocin neurons while the other group was untreated. Hypertensive animals exposed to CIH and treated with daily hypothalamic oxytocin neuron activation had lower blood pressure, faster heart rate recovery times after exercise, and improved indices of cardiac function compared with untreated hypertensive animals. Microarray analysis suggested that, compared with treated animals, untreated animals had gene expression profiles associated with cellular stress response activation, hypoxia-inducible factor stabilization, and myocardial extracellular matrix remodeling and fibrosis. In animals already presenting with CIH-induced hypertension, chronic activation of hypothalamic oxytocin neurons blunted the progression of hypertension and conferred cardioprotection after an additional 4 weeks of CIH exposure. These results have significant clinical translation for the treatment of cardiovascular disease in patients with obstructive sleep apnea.

Empagliflozin in heart failure with preserved ejection fraction: decoding its molecular mechanism of action using artificial intelligence

Abstract   Rationale The use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) to treat heart failure with preserved ejection fraction (HFpEF) is under investigation in ongoing clinical trials, but the exact mechanism of action is unclear. Here we aimed to use artificial intelligence (AI) to characterize the mechanism of action of empagliflozin in HFpEF at the molecular level. Methods We retrieved information regarding HFpEF pathophysiological motifs and differentially expressed genes/proteins, together with empagliflozin target information and bioflags, from specialized publicly available databases. Artificial neural networks and deep learning AI were used to model the molecular effects of empagliflozin in HFpEF. Results The model predicted that empagliflozin could reverse 59% of the protein alterations found in HFpEF. The effects of empagliflozin in HFpEF appeared to be predominantly mediated by inhibition of NHE1 (Na+/H+ exchanger 1), with SGLT2 playing a less prominent role. The elucidated molecular mechanism of action had an accuracy of 94%. Empagliflozin's pharmacological action mainly affected cardiomyocyte oxidative stress modulation, and greatly influenced cardiomyocyte stiffness, myocardial extracellular matrix remodelling, heart concentric hypertrophy, and systemic inflammation. Validation of these in silico data was performed in vivo in patients with HFpEF by measuring the declining plasma concentrations of NOS2, the NLPR3 inflammasome, and TGF-β1 during 12 months of empagliflozin treatment. Conclusion Using AI modelling, we identified that the main effect of empagliflozin in HFpEF treatment is exerted via NHE1 and is focused on cardiomyocyte oxidative stress modulation. These results support the potential use of empagliflozin in HFpEF. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos IIICentro de investigaciόn biomédica en red cardiovascular (CIBERCV) Summary figureTable 1

Decoding empagliflozin\u2019s molecular mechanism of action in heart failure with preserved ejection fraction using artificial intelligence

The use of sodium-glucose co-transporter 2 inhibitors to treat heart failure with preserved ejection fraction (HFpEF) is under investigation in ongoing clinical trials, but the exact mechanism of action is unclear. Here we aimed to use artificial intelligence (AI) to characterize the mechanism of action of empagliflozin in HFpEF at the molecular level. We retrieved information regarding HFpEF pathophysiological motifs and differentially expressed genes/proteins, together with empagliflozin target information and bioflags, from specialized publicly available databases. Artificial neural networks and deep learning AI were used to model the molecular effects of empagliflozin in HFpEF. The model predicted that empagliflozin could reverse 59% of the protein alterations found in HFpEF. The effects of empagliflozin in HFpEF appeared to be predominantly mediated by inhibition of NHE1 (Na+/H+ exchanger 1), with SGLT2 playing a less prominent role. The elucidated molecular mechanism of action had an accuracy of 94%. Empagliflozin’s pharmacological action mainly affected cardiomyocyte oxidative stress modulation, and greatly influenced cardiomyocyte stiffness, myocardial extracellular matrix remodelling, heart concentric hypertrophy, and systemic inflammation. Validation of these in silico data was performed in vivo in patients with HFpEF by measuring the declining plasma concentrations of NOS2, the NLPR3 inflammasome, and TGF-β1 during 12 months of empagliflozin treatment. Using AI modelling, we identified that the main effect of empagliflozin in HFpEF treatment is exerted via NHE1 and is focused on cardiomyocyte oxidative stress modulation. These results support the potential use of empagliflozin in HFpEF.

Myocardial Laminar Organization Is Retained in Angiotensin-Converting Enzyme Inhibitor Treated SHRs

Background: Cardiac remodeling underpinning progressive hypertensive heart disease alters the three-dimensional structure of the extracellular matrix, as well as the laminar organization of myocardial sheetlets. The effect of pharmacological intervention on microstructural remodeling is not known. Objective: To examine the changes in myocardial microstructure that occur as a result of hypertensive heart disease, and the effect of pharmacological treatment. Methods: The spontaneously hypertensive rat (SHR) model of hypertensive heart disease was studied, and compared with the normotensive Wistar Kyoto (WKY) rat, and SHRs treated with angiotensin converting enzyme inhibitors (TSHR). Cardiac magnetic resonance was used to assess cardiac function and ventricular geometry. Excised myocardium was stained (picrosirius red) for collagen and extended volume confocal microscopy used to produce high-resolution image stacks. Results: At 24 months, TSHRs had significantly greater ejection fraction (P < 0.05), and performed significantly less stroke work than the untreated diseased SHRs (P < 0.01). TSHR hearts displayed no increased collagen deposition between sheetlets at 14 months, unlike SHR hearts at the same age, which showed thick collagen and scarring. Laminar organization was retained in aged TSHR hearts, while it was progressively lost in aged SHR hearts. Conclusions: In aged SHRs, angiotensin converting enzyme inhibition attenuates remodeling of myocardial extracellular matrix, preserves the laminar organization of myocardial sheetlets, and helps to maintain normal cardiac function.

Remodeling of myocardial extracellular matrix and proteoglycans varies in pediatric versus adult patients with dilated cardiomyopathy

Background: Idiopathic dilated cardiomyopathy (DCM) is a common cause of heart failure in adult and pediatric patients, but the underlying mechanisms vary since pediatric DCM patients do not respond as well to treatments designed for the adult patient population.

Assessment of Remote Myocardium Heterogeneity in Patients with Ventricular Tachycardia Using Texture Analysis of Late Iodine Enhancement (LIE) Cardiac Computed Tomography (cCT) Images

PurposeDiffuse remodeling of myocardial extra-cellular matrix is largely responsible for left ventricle (LV) dysfunction and arrhythmias. Our hypothesis is that the texture analysis of late iodine enhancement (LIE) cardiac computed tomography (cCT) images may improve characterization of the diffuse extra-cellular matrix changes. Our aim was to extract volumetric extracellular volume (ECV) and LIE texture features of non-scarred (remote) myocardium from cCT of patients with recurrent ventricular tachycardia (rVT), and to compare these radiomic features with LV-function, LV-remodeling, and underlying cardiac disease.ProceduresForty-eight patients suffering from rVT were prospectively enrolled: 5/48 with idiopathic VT (IVT), 23/48 with post-ischemic dilated cardiomyopathy (ICM), 9/48 with idiopathic dilated cardiomyopathy (IDCM), and 11/48 with scars from a previous healed myocarditis (MYO). All patients underwent echocardiography to assess LV systolic and diastolic function and cCT with pre-contrast, angiographic, and LIE scan to obtain end-diastolic volume (EDV), ECV, and first-order texture parameters of Hounsfield Unit (HU) of remote myocardium in LIE [energy, entropy, HU-mean, HU-median, standard deviation (SD), and mean absolute deviation (MAD)].ResultsEnergy, HU mean, and HU median by cCT texture analysis correlated with ECV (rho = 0.5650, rho = 0.5741, rho = 0.5068; p < 0.0005). cCT-derived ECV, HU-mean, HU-median, SD, and MAD correlated directly to EDV by cCT and inversely to ejection fraction by echocardiography (p < 0.05). SD and MAD correlated with diastolic function by echocardiography (rho = 0.3837, p = 0.0071; rho = 0.3330, p = 0.0208). MYO and IVT patients were characterized by significantly lower values of SD and MAD when compared with ICM and IDCM patients, independently of LV-volume systolic and diastolic function.ConclusionsTexture analysis of LIE may expand cCT capability of myocardial characterization. Myocardial heterogeneity (SD and MAD) was associated with LV dilatation, systolic and diastolic function, and is able to potentially identify the different patterns of structural remodeling characterizing patients with rVT of different etiology.

Attenuation of the LPS-induced, ERK-mediated upregulation of fibrosis-related factors FGF-2, uPA, MMP-2, and MMP-9 by Carthamus tinctorius L in cardiomyoblasts.

Severe and potentially fatal hypotension and cardiac contractile dysfunction are common symptoms in patients with sepsis. LPS was previously found to dramatically upregulate expression of fibrosis-related factors FGF-2, uPA, MMP-2, and MMP-9 in primary cardiac fibroblasts. MMPs are capable of denaturing and degrading fibrillar collagens and other components of the extracellular matrix (ECM). Studies have shown that dysregulation of expression of MMPs is associated with development of myocardial extracellular matrix remodeling and cardiac fibrosis, which contribute to progression of heart failure. In this study, H9c2 cells and cardiac fibroblasts were divided into five treatment groups: control, LPS (1 μg/mL) and three concentrations of FCEtOH (Carthami Flos ethanolic extract) (31.25, 62.5, and 125 μg/mL). Phosphorylation of ERK-1/2 was observed to be rapidly induced upon treatment with LPS. In contrast, it was significantly suppressed by the administration of FCEtOH (125 μg/mL). Effects of FCEtOH on LPS-induced MMP-2 and MMP-9 expression in H9c2 cells occurred directly through ERK1/2 were determined. H9c2 cells were therefore pretreated with EGF-R to activate ERK pathway. Both protein levels of MMP-2 and MMP-9 and immunefluorescent signals of MMP-9 were significantly enhanced by EGFR. In contrast, MMP-2 and MMP-9 were significantly reduced after FCEtOH administration. Based on these findings, the authors concluded that FCEtOH elicits a protective effect against LPS-induced cardio-fibrosis through the ERK1/2 pathway. Carthamus tinctorius L may potentially serve as a cardio-protective agent against LPS- induced cardiac fibrosis. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 754-763, 2017.

The lymphocyte-to-monocyte ratio: An added value for death prediction in heart failure

Background and aimLeukocytes and their subpopulation have been long implicated in the progression of the syndrome of heart failure (HF), especially heart infiltration cells. Previous reports have suggested that they can predict worse outcome in patients with HF, and can also affect the function of other cells and myocardial extracellular matrix remodeling process. However, the lymphocyte-to-monocyte ratio (LMR) and its possible value as prognostic marker have not been evaluated. Methods and resultsA total of 390 patients with acute HF were recruited and followed for 6 months. Their total blood count with leukocyte differential was obtained. Two groups were formed according to the endpoints of HF death and optimal cut-off value of LMR, and were compared. A multivariate Cox-regression model was used to establish the prognostic value with the endpoints of HF and all-cause mortality. Median age of the patients was 78 years and 48.5% of them were men. No major difference was observed between the clinical characteristics of the two groups. Patients who died of HF had significantly higher values of B-type natriuretic peptide and lower values of LMR. Leukocyte and monocyte counts revealed a multivariate-adjusted risk for both endpoints, whereas relative lymphocyte counts had only significant value for all-cause mortality. The multivariate-adjusted hazard ratios for the 6-month HF and all-cause mortality in patients with LMR values < 2.0 were, respectively, 2.28 (95% CI: 1.25–4.15) and 2.39 (95% CI: 1.39–4.10). ConclusionOur results show that, upon discharge from hospital after an episode of acute HF, a lower value of LMR is independently associated with a higher risk of mortality within 6 months.

Dimeric [(68)Ga]DOTA-RGD peptide targeting αvβ 3 integrin reveals extracellular matrix alterations after myocardial infarction.

We evaluated a dimeric RGD-peptide, [(68)Ga]DOTA-E-[c(RGDfK)]2, for positron emission tomography (PET) imaging of myocardial integrin expression associated with extracellular matrix remodeling after myocardial infarction (MI) in rat. Male Sprague-Dawley rats were studied at 7 days and 4 weeks after MI induced by permanent ligation of the left coronary artery and compared with sham-operated controls. In vivo imaging revealed higher tracer uptake in the infarcted area than in the remote non-infarcted myocardium of the same rats both at 7 days (MI/remote ratio, 2.25 ± 0.24) and 4 weeks (MI/remote ratio, 2.13 ± 0.37) post-MI. Compared with sham-operated rats, tracer uptake was higher also in the remote, non-infarcted myocardium of MI rats both at 7 days and 4 weeks where it coincided with an increased interstitial fibrosis. Standardized uptake values correlated well with the results of tracer kinetic modeling. Autoradiography confirmed the imaging results showing 5.1 times higher tracer uptake in the infarcted than remote area. Tracer uptake correlated with the amount of β3 integrin subunits in the infarcted area. Our results show that integrin-targeting [(68)Ga]DOTA-E-[c(RGDfK)]2 is a potential tracer for monitoring of myocardial extracellular matrix remodeling after MI using PET.

Distinct structural and molecular features of the myocardial extracellular matrix remodeling in compensated and decompensated cardiac hypertrophy due to aortic stenosis

ObjectivesWe used immuhistochemistry and Western blot to study fibrillar and non-fibrillar collagens, collagen metabolism, matricellular proteins and regulatory factors of the ECM remodeling in left ventricular (LV) septum biopsies from 3 groups of patients with aortic valve stenosis (AS): (AS-1,n = 9): ejection fraction (EF) > 50%; AS-2,(n = 12): EF 30%–50%; AS-3,(n = 9): EF < 30%). Samples from 8 hearts with normal LV function served as controls. ResultsIn comparison with controls, fibrillar collagens I and III were progressively upregulated from compensated (AS-1) toward decompensated hypertrophy (AS-3). The collagenIII/collagen I ratio decreased 2-fold in the AS-2 and AS-3 groups as compared with AS-1 and controls. Non-fibrillar collagen IV was upregulated only in AS-3 patients, whereas collagen VI progressively increased from AS-1 to AS-3 group. Collagen synthesis in AS-3 was shifted to collagen I, while the maturation/degradation level was shifted to collagen III. RECK was downregulated only in AS-3 patients. Matricellular proteins tenascin and osteopontin were increased in all AS patients. However, thrombospondin 1, 4 and CTGF were increased only in AS-3. Only AS-3 patients were characterized by increased levels of TGFβ1 and downregulation of TGFβ3, TGFβ-activated kinase1 and Smad7. In contrast, Smad3 gradually increased from AS-1 toward AS-3. Similar trend of changes was observed for TNFα-R1 and TNFα-R2, whereas TNFα was diminished only in AS-2 and AS-3. ConclusionsDistinct changes in fibrillar collagen turnover, non-fibrillar collagens, matricellular proteins and the key regulatory profibrotic and anti-fibrotic factors of the myocardial ECM remodeling are involved in the transition from compensated to decompensated LV hypertrophy and HF in human patients with AS.

Osteopontin and Galectin‐3 Predict the Risk of Ventricular Tachycardia and Fibrillation in Heart Failure Patients with Implantable Defibrillators

Myocardial extracellular matrix remodelling provides electrical heterogeneity entailing ventricular tachycardia/fibrillation (VT/VF) in heart failure (HF) patients. Osteopontin (OPN) and Galectin-3 (Gal-3) are fibrosis markers and may reflect the extension of the arrhythmogenic substrate. We assessed whether plasma OPN and Gal-3 predict the risk of sustained VT/VF in a cohort of HF patients with implantable cardioverter-defibrillator (ICD). A total of 75 HF patients underwent pre-ICD implantation clinical evaluation and assessment of plasma OPN and Gal-3. The primary endpoint was the time to the occurrence of the first sustained VT/VF. Hazard ratios (HR) were derived from Cox proportional-hazards analysis. Patients with coronary artery disease (CAD) had higher plasma OPN (79.8 ± 44.0 ng/mL vs. 66.0 ± 31.8 ng/mL; P = 0.04). Both Gal-3 (r = -0.38; P = 0.01) and OPN (r = -0.27; p = 0.01) were negatively related to estimated glomerular filtration rate. After 29 ± 17 months, 20 patients (27%) reached the primary endpoint. Patients with VT/VF had higher plasma OPN and Gal-3 (97.4 ± 51.7 ng/mL vs. 65.9 ± 31.3 ng/mL; P = 0.002 and 19.7 ± 8.5 ng/mL vs. 16.2 ± 6.2 ng/mL; P = 0.05). In univariate analysis, OPN (log-OPN, HR: 32.4; 95%CI: 3.9-264.7; P = 0.001) and Gal-3 (HR: 1.05; 95%CI: 1.00-1.11; P = 0.04) predicted sustained VT/VF. In multivariable analysis, both OPN (HR: 41.4; 95%CI: 3.8-441.9; P = 0.002) and Gal-3 (HR: 1.06; 95%CI: 1.00-1.12; P = 0.03) retained their prognostic power after correction for age, sex, history of MI, EF, NYHA class, eGFR, use of ACE-I, and amiodarone. Plasma OPN and Gal-3 predict sustained VT/VF in HF patients at high risk for SCD. Larger prospective studies should outline the role of these biomarkers in predicting SCD on top of conventional risk stratification.

Lipocalin‐2 mediated myocardial extracellular matrix remodeling is correlated with Akt/P38 activity in hearts

Lipocalin‐2, a 25‐kDa glycoprotein secreted by adipocytes, belongs to the diversified lipocalin family. Although its physiological functions remain elusive, the expression of this protein is up‐regulated or rapidly induced under various pathological conditions. The impact of lipocalin‐2 on extracellular matrix (ECM) remodeling was determined in cardiac cells of wild type rats. Incubation of primary cultured fibroblasts with recombinant lipocalin‐2 promoted both intracellular collagen expression and extracellular collagen secretion. Up‐regulation of collagen production was also shown in infarcted cardiac tissues after permanent coronary artery ligation in wild type mice, which was positively correlated with enhanced levels of lipocalin‐2 in serum or the infracted heart tissues. The phosphorylation levels of Akt and/or P‐38 were significantly decreased by lipocalin‐2 treatment in primary cultured cardiomyocytes, fibroblasts or infarcted heart tissues. Gelatin zymography analysis of matrix metalloproteinase‐2 (MMP‐2) activity in conditioned medium collected from fibroblasts demonstrated that lipocalin‐2 treatment significantly induced MMP‐2 activity. These results demonstrate that lipocalin‐2 plays a role in mediating myocardial ECM remodeling and that the Akt/P‐38 pathways mediate these effects of the adipokine.

Tumor Necrosis Factor-α and Its Receptors 1 and 2

HomeCirculationVol. 119, No. 10Tumor Necrosis Factor-α and Its Receptors 1 and 2 Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBTumor Necrosis Factor-α and Its Receptors 1 and 2Yin and Yang in Myocardial Infarction? Rainer Schulz, MD and Gerd Heusch, MD Rainer SchulzRainer Schulz From the Institut für Pathophysiologie, Universitätsklinikum Essen, Essen, Germany. Search for more papers by this author and Gerd HeuschGerd Heusch From the Institut für Pathophysiologie, Universitätsklinikum Essen, Essen, Germany. Search for more papers by this author Originally published2 Mar 2009https://doi.org/10.1161/CIRCULATIONAHA.108.846105Circulation. 2009;119:1355–1357Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: March 2, 2009: Previous Version 1 In healthy hearts, tumor necrosis factor-α (TNF-α) concentration is low, and TNF-α is mainly located in endothelium and resident mast cells.1 TNF-α receptors (TNFRs) 1 (TNFR1) and 2 (TNFR2) are expressed on most cardiac cells, including cardiomyocytes.2 During myocardial ischemia, preformed TNF-α is released within minutes from resident mast cells and macrophages.3 With persistent ischemia, TNF-α also originates from cardiomyocytes.4 In rats after myocardial infarction (MI), TNFR1 density is increased for 10 days, whereas TNFR2 density remains unchanged.5 In contrast, TNFR1 and TNFR2 are both downregulated in the failing heart, whereas soluble TNFRs are increased6 owing to proteolytic cleavage of cardiomyocyte TNFR and release from circulating exosome-like vesicles.7 Increased soluble TNFRs decrease TNF-α bioactivity while at the same time prolonging its half-life.8Article p 1386TNF-α and Myocardial Ischemia/ Reperfusion InjuryTNF-α contributes to both reversible (contractile dysfunction4,9) and irreversible (MI) injury.1 Preischemic treatment with TNF-α antibodies10 or soluble TNFR1,11 permanent TNF-α knockout,12 or knockout of TNFR1 but not TNFR213 all reduce infarct size. The latter finding highlights the functional difference of TNFR1 and TNFR2 activation for ischemia/reperfusion injury: Only TNFR1 signaling is detrimental (Figure). Download figureDownload PowerPointFigure. Signaling cascade activated (→) or inhibited (⊣) by TNFR1 (red) or TNFR2 (blue) activation. sTNFR1 indicates soluble TNFR1; sTNFR2, soluble TNFR2; S1-P, sphingosine-1-phosphate; NF-κB, nuclear factor-κB; SOCS3, suppressor of cytokine signaling 3; ROS, reactive oxygen species; Akt-P, phosphorylated Akt, a homologue of the transforming v-Akt; NADPH-Ox, NADPH oxidase; STAT3-P, phosphorylated signal transducer and activator of transcription; Jnk-P, phosphorylated c-jun N-terminal kinase; p38-P, phosphorylated mitogen-activated protein kinase; Erk-P, phosphorylated extracellular signal-regulated kinase; PKC, protein kinase C; CamK, calcium/calmodulin-dependent kinase; MMP-2/9, matrix metalloproteinases 2 and 9; and IL-6, interleukin 6. Red indicates proteins involved in apoptosis; purple, proteins involved in growth; green, proteins involved in contractile function; blue, protein involved in inflammation; and yellow, proteins involved in extracellular matrix turnover.TNF-α and CardioprotectionAlthough TNF-α aggravates acute ischemia/reperfusion injury, preconditioning with TNF-α reduces infarct size.1 In addition, accumulation of endogenous TNF-α after coronary microembolization reduces infarct size.9 Finally, the protection of delayed ischemic preconditioning is absent after pretreatment with TNF-α antibodies and in TNF-α–, TNFR1-, and TNFR2-knockout mice13; the latter result reflects the involvement of both TNFRs in cardioprotection.13,14TNF-α and Permanent Coronary OcclusionTransfection with soluble TNFR1 reduces infarct size 3 weeks after MI in rats8 but not in mice.15 Neither genetic ablation of TNF-α16 nor knockout of TNFR117 or TNFR218 alters infarct size when measured 1 day17 or several weeks after coronary ligation.16–18 However, infarct size after 1 day is increased with knockout of both TNFRs and is associated with increased cardiomyocyte apoptosis in the area at risk.19With permanent coronary occlusion, 40% to 70% of mice die within 10 days after MI,15–18,20 and >50% of them die of cardiac rupture.15,16,18 Reduction of TNF-α bioactivity by adenoviral transfection with soluble TNFR1 promotes rather than attenuates cardiac rupture by inhibiting reactive fibrosis and reduces survival within 7 days after MI in male mice.15 In contrast, genetic ablation of TNF-α16 or TNFR1 knockout17,18 increases post-MI survival, without reducing the rate of cardiac rupture.18 In contrast to TNFR knockout, matrix metalloproteinase-2 knockout reduces cardiac rupture and increases survival after MI.20Elevated TNF-α contributes to chronic left ventricular (LV) dysfunction after MI through a local inflammatory response,16 increased matrix metalloproteinase-2 activity, matrix and collagen degradation,16,20 and cardiomyocyte apoptosis.16 TNF-α inhibition with etanercept immediately after MI reduces leukocyte infiltration and extracellular matrix degradation and preserves cardiac function 6 weeks after MI in rats.21 Similarly, TNF-α blockade with soluble TNFR2 attenuates hemodynamic derangements in the first week after MI in rats but does not attenuate LV dilatation 10 weeks after MI.22 In contrast, adenoviral transfection with soluble TNFR1 starting 7 days after MI exacerbates LV dysfunction and remodeling.15TNFR1 knockout attenuates contractile dysfunction after MI,17,18 whereas TNFR2 knockout exaggerates ventricular dilatation and dysfunction. Upregulated transcript levels of inflammatory markers after MI are reduced in TNFR1-knockout mice but further enhanced in TNFR2-knockout mice. Thus, TNF-α worsens LV remodeling via TNFR1 and improves it via TNFR2 after MI.18Hamid and coworkers in their elegant study in the present issue of Circulation now further delineate the ambivalent role of TNFR1 and TNFR2 in post-MI remodeling in male mice.23 Knockout of TNFR1 improved LV ejection fraction; reduced LV dilatation, cardiomyocyte hypertrophy and apoptosis, fibrosis, and inflammation; and ultimately resulted in improved survival after MI. In contrast, knockout of TNFR2 increased LV dilatation, cardiomyocyte hypertrophy and apoptosis, and fibrosis in the remote myocardium but did not affect systolic LV function. However, survival was also increased in TNFR2-knockout mice, and both TNFR-knockout mice had less reactive oxygen species formation and improved diastolic LV pressure. Importantly, Hamid and coworkers23 analyzed the signaling of TNFR1 and TNFR2 activation (Figure) and highlighted the divergent effects of TNFR1 and TNFR2 activation on stress kinase activation, nuclear signaling, and cardiomyocyte death pathways.Some questions remain: Is blockade of TNF-α bioactivity beneficial or deleterious? Increased TNF-α induces contractile dysfunction1 up to heart failure,24,25 and TNFR1 activation is primarily responsible for these detrimental effects.25 However, basal TNF-α improves contractile function via TNFR1 activation,26 and endogenous TNF-α contributes to the protection afforded by preconditioning through both TNFRs13; in addition, elimination of both TNFRs increases cardiomyocyte apoptosis.19 Thus, apart from signaling through TNFR1 or TNFR2, TNF-α can exert both beneficial and deleterious actions, depending on its concentration and duration of exposure.Are time and localization of increased TNF-α important? TNF-α remains elevated for weeks in the infarcted area, whereas it decreases in the peri-infarct area 1 week after MI and remains only slightly above basal values.5 Contractile dysfunction and LV dilatation coincide with the peak increase of TNF-α after MI.22 TNF-α in the infarcted area contributes to cardiomyocyte apoptosis, whereas TNF-α in the peri-infarct area might stimulate fibroblasts,27 thereby stabilize the infarcted area, and attract stem cells28 for cardiac repair and suppression of inflammation.29 Elevated TNF-α in the peri-infarct area depresses contractile function, induces cardiomyocyte apoptosis, and triggers fibrosis; however, when subsequently reduced again, TNF-α in the peri-infarct area might contribute to preservation of contractile function.26What is the contribution of cardiac rupture and arrhythmias to the impact of TNF-α on mortality? Hamid and coworkers23 suggest that less cardiac rupture was responsible for improved survival in TNFR knockouts. However, neither TNFR1 nor TNFR2 knockout affects the rate of cardiac rupture after MI,18 and blockade of TNF-α bioactivity by adenoviral transfer of soluble TNFR1 even increases the rate of cardiac rupture.15 An alternative explanation for the improved survival after MI in TNFR knockouts relates to a reduced incidence of arrhythmias. In post-MI rats, ventricular arrhythmias coincide with the secretion of TNF-α,30 and TNF-α promotes action potential prolongation through formation of reactive oxygen species in rat ventricular myocytes.31 Thus, diminished reactive oxygen species formation in TNFR knockouts, as shown by Hamid and coworkers,23 could restore normal repolarization and reduce arrhythmias. ECG tracings of TNFR1 and TNFR2 knockouts after MI could help identify the underlying cause.Are gender and age important for the actions of TNF-α? The expression of myocardial TNFR is higher in male than in female hearts, and such differential expression may contribute to sex differences in the severity of congestive heart failure and mortality.2,17 Indeed, TNF-α infusion depresses contractile function in male but not female mouse hearts.32 TNF-α–overexpressing mice develop progressive cardiomyocyte hypertrophy and LV dilatation, as well as increased collagen synthesis and deposition, along with marked diastolic dysfunction. Anti-TNF-α treatment prevents changes in extracellular matrix and preserves diastolic function, as did TNFR1 and TNFR2 knockout in the present study; however, this beneficial effect is only observed in young and not in old mice,24 which suggests a sex- and age-dependent signaling cascade after TNFR activation.ConclusionsIndeed, TNF-α and TNFR activation have an ambivalent role in MI. Excessive TNF-α expression and subsequent cardiomyocyte TNFR1 activation are detrimental, whereas a lower TNF-α concentration and subsequent cardiomyocyte TNFR2 activation are protective. TNF-α–induced fibrosis and attraction of stem cells might stabilize the infarcted area, while contributing to structural remodeling and diastolic dysfunction in remote myocardium. Apart from its receptor subtype, the action of TNF-α depends on its concentration, duration of exposure, and localization, as well as on the sex and age of the affected individual. Therefore, it is not surprising that clinical trials in chronic heart failure patients using compounds that antagonize TNF-α, including the TNF-α antibody infliximab and the soluble recombinant TNF-α receptor etanercept, revealed disappointing results, which supports the ambivalent effect of TNF-α.33The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.DisclosuresNone.FootnotesCorrespondence to Professor Dr Rainer Schulz, Institut für Pathophysiologie, Universitätsklinikum Essen, Hufelandstrasse 55, 45122 Essen, Germany. E-mail [email protected] References 1 Schulz R. TNFα in myocardial ischemia/reperfusion: damage vs. protection. J Mol Cell Cardiol. 2008; 45: 712–714.CrossrefMedlineGoogle Scholar2 Kadokami T, McTiernan CF, Kubota T, Frye CS, Feldman AM. Sex-related survival differences in murine cardiomyopathy are associated with differences in TNF-receptor expression. J Clin Invest. 2000; 106: 589–597.CrossrefMedlineGoogle Scholar3 Gilles S, Zahler S, Welsch U, Sommerhoff CP, Becker BF. Release of TNF-alpha during myocardial reperfusion depends on oxidative stress and is prevented by mast cell stabilizers. Cardiovasc Res. 2003; 60: 608–616.CrossrefMedlineGoogle Scholar4 Dorge H, Schulz R, Belosjorow S, Post H, van de Sand A, Konietzka I, Frede S, Hartung T, Vinten-Johansen J, Youker KA, Entman ML, Erbel R, Heusch G. Coronary microembolization: the role of TNF-alpha in contractile dysfunction. J Mol Cell Cardiol. 2002; 34: 51–62.CrossrefMedlineGoogle Scholar5 Irwin MW, Mak S, Mann DL, Qu R, Penninger JM, Yan A, Dawood F, Wen WH, Shou Z, Liu P. Tissue expression and immunolocalization of tumor necrosis factor-α in postinfarction dysfunctional myocardium. Circulation. 1999; 99: 1492–1498.CrossrefMedlineGoogle Scholar6 Torre-Amione G, Kapadia S, Lee J, Durand JB, Bies RD, Young JB, Mann DL. Tumor necrosis factor-α and tumor necrosis factor receptors in the failing human heart. Circulation. 1996; 93: 704–711.CrossrefMedlineGoogle Scholar7 Zhang J, Hawari FI, Shamburek RD, Adamik B, Kaler M, Islam A, Liao DW, Rouhani FN, Ingham M, Levine SJ. Circulating TNFR1 exosome-like vesicles partition with the LDL fraction of human plasma. Biochem Biophys Res Commun. 2008; 366: 579–584.CrossrefMedlineGoogle Scholar8 Sugano M, Tsuchida K, Hata T, Makino N. In vivo transfer of soluble TNF-alpha receptor 1 gene improves cardiac function and reduces infarct size after myocardial infarction in rats. FASEB J. 2004; 18: 911–913.CrossrefMedlineGoogle Scholar9 Skyschally A, Gres P, Hoffmann S, Haude M, Erbel R, Schulz R, Heusch G. Bidirectional role of tumor necrosis factor-alpha in coronary microembolization: progressive contractile dysfunction versus delayed protection against infarction. Circ Res. 2007; 100: 140–146.LinkGoogle Scholar10 Belosjorow S, Bolle I, Duschin A, Heusch G, Schulz R. TNF-alpha antibodies are as effective as ischemic preconditioning in reducing infarct size in rabbits. Am J Physiol Heart Circ Physiol. 2003; 284: H927–H930.CrossrefMedlineGoogle Scholar11 Sugano M, Hata T, Tsuchida K, Suematsu N, Oyama J, Satoh S, Makino N. Local delivery of soluble TNF-alpha receptor 1 gene reduces infarct size following ischemia/reperfusion injury in rats. Mol Cell Biochem. 2004; 266: 127–132.CrossrefMedlineGoogle Scholar12 Maekawa N, Wada H, Kanda T, Niwa T, Yamada Y, Saito K, Fujiwara H, Sekikawa K, Seishima M. Improved myocardial ischemia/reperfusion injury in mice lacking tumor necrosis factor-alpha. J Am Coll Cardiol. 2002; 39: 1229–1235.CrossrefMedlineGoogle Scholar13 Flaherty MP, Guo Y, Tiwari S, Rezazadeh A, Hunt G, Sanganalmath SK, Tang XL, Bolli R, Dawn B. The role of TNF-alpha receptors p55 and p75 in acute myocardial ischemia/reperfusion injury and late preconditioning. J Mol Cell Cardiol. 2008; 45: 735–741.CrossrefMedlineGoogle Scholar14 Heusch G, Boengler K, Schulz R. Cardioprotection: nitric oxide, protein kinases, and mitochondria. Circulation. 2008; 118: 1915–1919.LinkGoogle Scholar15 Monden Y, Kubota T, Tsutsumi T, Inoue T, Kawano S, Kawamura N, Ide T, Egashira K, Tsutsui H, Sunagawa K. Soluble TNF receptors prevent apoptosis in infiltrating cells and promote ventricular rupture and remodeling after myocardial infarction. Cardiovasc Res. 2007; 73: 794–805.CrossrefMedlineGoogle Scholar16 Sun M, Dawood F, Wen WH, Chen M, Dixon I, Kirshenbaum LA, Liu PP. Excessive tumor necrosis factor activation after infarction contributes to susceptibility of myocardial rupture and left ventricular dysfunction. Circulation. 2004; 110: 3221–3228.LinkGoogle Scholar17 Ramani R, Mathier M, Wang P, Gibson G, Tögel S, Dawson J, Bauer A, Alber S, Watkins SC, McTiernan CF, Feldman AM. Inhibition of tumor necrosis factor receptor-1-mediated pathways has beneficial effects in a murine model of postischemic remodeling. Am J Physiol Heart Circ Physiol. 2004; 287: H1369–H1377.CrossrefMedlineGoogle Scholar18 Monden Y, Kubota T, Inoue T, Tsutsumi T, Kawano S, Ide T, Tsutsui H, Sunagawa K. Tumor necrosis factor-alpha is toxic via receptor 1 and protective via receptor 2 in a murine model of myocardial infarction. Am J Physiol Heart Circ Physiol. 2007; 293: H743–H753.CrossrefMedlineGoogle Scholar19 Kurrelmeyer KM, Michael LH, Baumgarten G, Taffet GE, Peschon JJ, Sivasubramanian N, Entman ML, Mann DL. Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction. Proc Natl Acad Sci U S A. 2000; 97: 5456–5461.CrossrefMedlineGoogle Scholar20 Hayashidani S, Tsutsui H, Ikeuchi M, Shiomi T, Matsusaka H, Kubota T, Imanaka-Yoshida K, Itoh T, Takeshita A. Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction. Am J Physiol Heart Circ Physiol. 2003; 285: H1229–H1235.CrossrefMedlineGoogle Scholar21 Berry MF, Woo YJ, Pirolli TJ, Bish LT, Moise MA, Burdick JW, Morine KJ, Jayasankar V, Gardner TJ, Sweeney HL. Administration of a tumor necrosis factor inhibitor at the time of myocardial infarction attenuates subsequent ventricular remodeling. J Heart Lung Transplant. 2004; 23: 1061–1068.CrossrefMedlineGoogle Scholar22 Berthonneche C, Sulpice T, Boucher F, Gouraud L, de Leiris J, O'Connor SE, Herbert JM, Janiak P. New insights into the pathological role of TNF-alpha in early cardiac dysfunction and subsequent heart failure after infarction in rats. Am J Physiol Heart Circ Physiol. 2004; 287: H340–H350.CrossrefMedlineGoogle Scholar23 Hamid T, Gu Y, Ortines RV, Bhattacharya C, Wang G, Xuan Y-T, Prabhu SD. Divergent tumor necrosis factor receptor–related remodeling responses in heart failure: role of nuclear factor-κB and inflammatory activation. Circulation. 2009; 119: 1386–1397.LinkGoogle Scholar24 Li YY, Feng YQ, Kadokami T, McTiernan CF, Draviam R, Watkins SC, Feldman AM. Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor alpha can be modulated by anti-tumor necrosis factor alpha therapy. Proc Natl Acad Sci U S A. 2000; 97: 12746–12751.CrossrefMedlineGoogle Scholar25 Higuchi Y, McTiernan CF, Frye CB, McGowan BS, Chan TO, Feldman AM. Tumor necrosis factor receptors 1 and 2 differentially regulate survival, cardiac dysfunction, and remodeling in transgenic mice with tumor necrosis factor-α–induced cardiomyopathy. Circulation. 2004; 109: 1892–1897.LinkGoogle Scholar26 Pinz I, Wax SD, Anderson P, Ingwall JS. Low over-expression of TNFα in the mouse heart increases contractile performance via TNFR1. J Cell Biochem. 2008; 105: 99–107.CrossrefMedlineGoogle Scholar27 Gurantz D, Cowling RT, Varki N, Frikovsky E, Moore CD, Greenberg BH. IL-1β and TNF-α upregulate angiotensin II type 1 (AT1) receptors on cardiac fibroblasts and are associated with increased AT1 density in the post-MI heart. J Mol Cell Cardiol. 2005; 38: 505–515.CrossrefMedlineGoogle Scholar28 Chen Y, Ke Q, Yang Y, Rana JS, Tang J, Morgan JP, Xiao YF. Cardiomyocytes overexpressing TNF-alpha attract migration of embryonic stem cells via activation of p38 and c-Jun amino-terminal kinase. FASEB J. 2003; 17: 2231–2239.CrossrefMedlineGoogle Scholar29 Bao C, Guo J, Lin G, Hu M, Hu Z. TNFR gene-modified mesenchymal stem cells attenuate inflammation and cardiac dysfunction following MI. Scand Cardiovasc J. 2008; 42: 56–62.CrossrefMedlineGoogle Scholar30 Xiao H, Chen Z, Liao Y, Cheng X, Liu K, Wang Y, Wang M, Guo H. Positive correlation of tumor necrosis factor-alpha early expression in myocardium and ventricular arrhythmias in rats with acute myocardial infarction. Arch Med Res. 2008; 39: 285–291.CrossrefMedlineGoogle Scholar31 Fernandez-Velasco M, Ruiz-Hurtado G, Hurtado O, Moro MA, Delgado C. TNF-alpha downregulates transient outward potassium current in rat ventricular myocytes through iNOS overexpression and oxidant species generation. Am J Physiol Heart Circ Physiol. 2007; 293: H238–H245.CrossrefMedlineGoogle Scholar32 Wang M, Tsai BM, Crisostomo PR, Meldrum DR. Tumor necrosis factor receptor 1 signaling resistance in the female myocardium during ischemia. Circulation. 2006; 114 (suppl I): I-282–I-289.LinkGoogle Scholar33 Mousa SA, Goncharuk O, Miller D. Recent advances of TNF-alpha antagonists in rheumatoid arthritis and chronic heart failure. Expert Opin Biol Ther. 2007; 7: 617–625.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Liberale L, Ministrini S, Carbone F, Camici G and Montecucco F (2021) Cytokines as therapeutic targets for cardio- and cerebrovascular diseases, Basic Research in Cardiology, 10.1007/s00395-021-00863-x, 116:1, Online publication date: 1-Dec-2021. Gouweleeuw L, Wajant H, Maier O, Eisel U, Blankesteijn W and Schoemaker R (2021) Effects of selective TNFR1 inhibition or TNFR2 stimulation, compared to non-selective TNF inhibition, on (neuro)inflammation and behavior after myocardial infarction in male mice, Brain, Behavior, and Immunity, 10.1016/j.bbi.2021.01.001, 93, (156-171), Online publication date: 1-Mar-2021. Sheng X, Fan T, Jin X and Huang T (2020) Identification of Key Genes Involved in Acute Myocardial Infarction by Comparative Transcriptome Analysis, BioMed Research International, 10.1155/2020/1470867, 2020, (1-10), Online publication date: 6-Oct-2020. Mendieta G, Ben-Aicha S, Gutiérrez M, Casani L, Aržanauskaitė M, Carreras F, Sabate M, Badimon L and Vilahur G (2020) Intravenous Statin Administration During Myocardial Infarction Compared With Oral Post-Infarct Administration, Journal of the American College of Cardiology, 10.1016/j.jacc.2020.01.042, 75:12, (1386-1402), Online publication date: 1-Mar-2020. Ravi S, Willis M and Schisler J (2019) Fibrotic Signaling in Cardiomyopathies Fibrosis in Disease, 10.1007/978-3-319-98143-7_10, (273-317), . Van Taunay J, Albelda M, Frias J and Lipinski M (2018) Biologics and Cardiovascular Disease, Journal of Cardiovascular Pharmacology, 10.1097/FJC.0000000000000595, 72:2, (77-85), Online publication date: 1-Aug-2018. Hadebe N, Cour M and Lecour S (2018) The SAFE pathway for cardioprotection: is this a promising target?, Basic Research in Cardiology, 10.1007/s00395-018-0670-5, 113:2, Online publication date: 1-Mar-2018. Torrey H, Butterworth J, Mera T, Okubo Y, Wang L, Baum D, Defusco A, Plager S, Warden S, Huang D, Vanamee E, Foster R and Faustman D (2017) Targeting TNFR2 with antagonistic antibodies inhibits proliferation of ovarian cancer cells and tumor-associated T regs , Science Signaling, 10.1126/scisignal.aaf8608, 10:462, Online publication date: 17-Jan-2017. Alánová P, Chytilová A, Neckář J, Hrdlička J, Míčová P, Holzerová K, Hlaváčková M, Macháčková K, Papoušek F, Vašinová J, Benák D, Nováková O and Kolář F (2017) Myocardial ischemic tolerance in rats subjected to endurance exercise training during adaptation to chronic hypoxia, Journal of Applied Physiology, 10.1152/japplphysiol.00671.2016, 122:6, (1452-1461), Online publication date: 1-Jun-2017. Butt N, Bache-Mathiesen L, Nordrehaug J, Tuseth V, Munk P, Bonarjee V, Hall T, Jensen S, Halvorsen S, Firat H, Atar D and Larsen A (2017) Administration of the Mitochondrial Permeability Transition Pore Inhibitor, TRO40303, prior to Primary Percutaneous Coronary Intervention, Does Not Affect the Levels of Pro-Inflammatory Cytokines or Acute-Phase Proteins, Cardiology, 10.1159/000475460, 138:2, (122-132), . Sandoval-Pinto E, Padilla-Gutiérrez J, Valdés-Alvarado E, García-González I, Valdez-Haro A, Muñoz-Valle J, Flores-Salinas H, Brennan-Bourdon L and Valle Y (2016) Association of the −1031T>C polymorphism and soluble TNF-α levels with Acute Coronary Syndrome, Cytokine, 10.1016/j.cyto.2015.11.014, 78, (37-43), Online publication date: 1-Feb-2016. Zheng D, Zhao J, Yang J, Wang M and Zhang X (2016) Enhanced ADAM17 expression is associated with cardiac remodeling in rats with acute myocardial infarction, Life Sciences, 10.1016/j.lfs.2016.02.097, 151, (61-69), Online publication date: 1-Apr-2016. Jin H, Chen L, Zhang Z, Xu Y, Song B, Xu R, Oudit G, Gao P, Zhu D and Zhong J (2015) Deletion of angiotensin-converting enzyme 2 exacerbates renal inflammation and injury in apolipoprotein E-deficient mice through modulation of the nephrin and TNF-alpha-TNFRSF1A signaling, Journal of Translational Medicine, 10.1186/s12967-015-0616-8, 13:1, Online publication date: 1-Dec-2015. Chytilová A, Borchert G, Mandíková-Alánová P, Hlaváčková M, Kopkan L, Khan M, Imig J, Kolář F and Neckář J (2015) Tumour necrosis factor- α contributes to improved cardiac ischaemic tolerance in rats adapted to chronic continuous hypoxia , Acta Physiologica, 10.1111/apha.12489, 214:1, (97-108), Online publication date: 1-May-2015. Liu Q, Wang T, Yu H, Liu B and Jia R (2014) Interaction Between Interleukin-1 Beta and Angiotensin II Receptor 1 in Hypothalamic Paraventricular Nucleus Contributes to Progression of Heart Failure, Journal of Interferon & Cytokine Research, 10.1089/jir.2013.0159, 34:11, (870-875), Online publication date: 1-Nov-2014. Schönberger T, Jürgens T, Müller J, Armbruster N, Niermann C, Gorressen S, Sommer J, Tian H, di Paolo G, Scheller J, Fischer J, Gawaz M and Elvers M (2014) Pivotal Role of Phospholipase D1 in Tumor Necrosis Factor-α–Mediated Inflammation and Scar Formation after Myocardial Ischemia and Reperfusion in Mice, The American Journal of Pathology, 10.1016/j.ajpath.2014.06.005, 184:9, (2450-2464), Online publication date: 1-Sep-2014. Duerrschmid C, Crawford J, Reineke E, Taffet G, Trial J, Entman M and Haudek S (2013) TNF receptor 1 signaling is critically involved in mediating angiotensin-II-induced cardiac fibrosis, Journal of Molecular and Cellular Cardiology, 10.1016/j.yjmcc.2013.01.006, 57, (59-67), Online publication date: 1-Apr-2013. Liu H, Luiten P, Eisel U, Dejongste M and Schoemaker R (2013) Depression after myocardial infarction: TNF-α-induced alterations of the blood–brain barrier and its putative therapeutic implications, Neuroscience & Biobehavioral Reviews, 10.1016/j.neubiorev.2013.02.004, 37:4, (561-572), Online publication date: 1-May-2013. Diamantopoulos A, Larsen A and Omdal R (2013) Is it safe to use TNF-α blockers for systemic inflammatory disease in patients with heart failure? Importance of dosage and receptor specificity, International Journal of Cardiology, 10.1016/j.ijcard.2012.11.112, 167:5, (1719-1723), Online publication date: 1-Sep-2013. Syriga M and Mavroidis M (2013) Complement System Activation in Cardiac and Skeletal Muscle Pathology: Friend or Foe? Complement Therapeutics, 10.1007/978-1-4614-4118-2_14, (207-218), . Ljung L, Simard J, Jacobsson L, Rantapää-Dahlqvist S and Askling J (2011) Treatment with tumor necrosis factor inhibitors and the risk of acute coronary syndromes in early rheumatoid arthritis, Arthritis & Rheumatism, 10.1002/art.30654, 64:1, (42-52), Online publication date: 1-Jan-2012. Khanna A, Xu J and Mehra M (2011) Antioxidant N-acetyl cysteine reverses cigarette smoke-induced myocardial infarction by inhibiting inflammation and oxidative stress in a rat model, Laboratory Investigation, 10.1038/labinvest.2011.146, 92:2, (224-235), Online publication date: 1-Feb-2012. Lacerda L, Opie L and Lecour S (2012) Influence of Tumour Necrosis Factor Alpha on the Outcome of Ischaemic Postconditioning in the Presence of Obesity and Diabetes, Experimental Diabetes Research, 10.1155/2012/502654, 2012, (1-10), . Villarreal-Calderon R, Reed W, Palacios-Moreno J, Keefe S, Herritt L, Brooks D, Torres-Jardón R and Calderón-Garcidueñas L (2012) Urban air pollution produces up-regulation of myocardial inflammatory genes and dark chocolate provides cardioprotection, Experimental and Toxicologic Pathology, 10.1016/j.etp.2010.09.002, 64:4, (297-306), Online publication date: 1-May-2012. Villarreal-Calderon R, Dale G, Delgado-Ch&aacute;vez R, Torres-Jard&oacute;n R, Zhu H, Herritt L, G&oacute;nzalez-Maciel A, Reynoso-Robles R, Yuan Y, Wang J, Solorio-L&oacute;pez E, Medina-Cortina H and Calder&oacute;n-Garcidue&ntilde;as L (2012) Intra-city Differences in Cardiac Expression of Inflammatory Genes and Inflammasomes in Young Urbanites: A Pilot Study, Journal of Toxicologic Pathology, 10.1293/tox.25.163, 25:2, (163-173), . Kuzmin V, Abramochkin D, Mitrochin V, Tian B, Makarenko E, Kovalchuk L, Khoreva M, Nikonova A, Kalugin L, Lysenko N, Lozinsky I, Rozanov A, Arutyunov G, Kiseleva I and Kamkin A (2012) The Role of Proinflammatory Cytokines in Regulation of Cardiac Bioelectrical Activity: Link to Mechanoelectrical Feedback Mechanical Stretch and Cytokines, 10.1007/978-94-007-2004-6_5, (107-153), . Parajuli N, Yuan Y, Zheng X, Bedja D and Cai Z (2012) Phosphatase PTEN is critically involved in post-myocardial infarction remodeling through the Akt/interleukin-10 signaling pathway, Basic Research in Cardiology, 10.1007/s00395-012-0248-6, 107:2, Online publication date: 1-Mar-2012. Martin M and Blaxall B (2012) Cardiac Intercellular Communication: Are Myocytes and Fibroblasts Fair-Weather Friends?, Journal of Cardiovascular Translational Research, 10.1007/s12265-012-9404-5, 5:6, (768-782), Online publication date: 1-Dec-2012. Kang Y, Gao F, Li H, Cardinale J, Elks C, Zang W, Yu X, Xu Y, Qi J, Yang Q and Francis J (2011) NF-κB in the paraventricular nucleus modulates neurotransmitters and contributes to sympathoe

Effect of carvedilol on cardiac metalloproteinases and tissue inhibitors of metalloproteinases after myocardial infarction in rats

Objective:To investigate the effect of carvedilol on expression of cardiac matrix metalloproteinases(MMPs)and tissue inhibitors of metalloproteinases(TIMPs)after myocardial infarction in rats.Methods:An animal model of acute myocar- dial infarction(AMI)was established by descending left coronary artery ligation in 24 rats and they were divided into carvedilol (10 mg·kg~(-1)·d~(-1))group(n=12)and normal saline group(n=12).Sham operated group(n=9)received the same proce- dure but with no ligation.All animals were treated for 6 weeks via a gastric lavage.Heart function and hemodynamic parame- ters were determined after 6 weeks.The protein expression of cardiac MMP-2,MMP-9 and TIMP-2 was detected by immuno- histoehemical analysis in AMI groups,and the MMPs activities were assessed by zymography.Gene expression of myocardial MMPs/TIMPs(MMP-2,9 and TIMP-1,2)and cytokines(TNF-α,IL-1β)were measured by real-time quantitative PCR.Re- suits:Compared with Sham-operated group,earvedilol group had significantly higher left ventricular end-diastolic pressure(LV- EDP)and lower LV upstroke velocity(+dp/dt_(max))and LV descent velocity(-dp/dt_(max))(P0.01).Activities of MMP-2 and MMP-9,protein expression of MMP-2,MMP-9 and TIMP-2,and mRNA expression of MMP-2,MMP-9,TIMP-1,TIMP-2, IL-1β,and TNF-αwere all higher in carvedilol group compared with sham-operated group(P0.05).Compared with normal saline group,carvedilol group had lower LVEDP(P0.01),higher+dp/dt_(max),-dp/dt_(max)(P0.05),lower activities of MMP-2,MMP-9(P0.01),lower protein expression of MMP-2,MMP-9 and TIMP-2,and lower mRNA expression of MMP-2.MMP-9.TIMP-2,IL-1β,TIMP-1,and TNF-α(MMP-9 P0.01,others P0.05).Conclusion:Carvedilol can obvious ly decrease cardiac expression of MMP-2 and MMP-9 and slightly decrease expression of TIMPs;it can also decrease secretion of MMPs through decreasing IL-1βand TNF-αexpression,thus prevents myocardial extracellular matrix remodeling,reverses ventricular remodeling,and subsequently improves cardiac function.

IGF-II/mannose 6-phosphate receptor activation induces metalloproteinase-9 matrix activity and increases plasminogen activator expression in H9c2 cardiomyoblast cells

The IGF-II/mannose 6-phosphate receptor (IGF2R) function in extracellular matrix (ECM) remodeling is known to occur as a result of transforming growth factor-beta (TGF-beta) activation and plasmin in the proteolytic cleavage level caused by the interaction between latent TGF-beta and urokinase plasminogen activator receptor (uPAR) respectively. In one of our previous studies, we found IGF-II and IGF2R dose-dependently correlated with the progression of pathological hypertrophy remodeling following complete abdominal aorta ligation. However, how this IGF2R signaling pathway responds specifically to IGF-II and regulates the myocardial ECM remodeling process is unclear. We found that IGF2R was aberrantly expressed in myocardial infarction scars. The matrix metalloproteinase-9 (MMP-9) zymographic activity was elevated in H9c2 cardiomyoblast cells treated with IGF-II, but not IGF-I. Treatment with Leu27IGF-II, an IGF2R specifically binding IGF-II analog, resulted in significant time-dependent increases in the MMP-9, tissue-type plasminogen activator (tPA), and urokinase plasminogen activator (uPA); and a reduction in the tissue inhibitor of matrix metalloproteinases-2 (TIMP-2) protein expression. Furthermore, IGF2R expression inhibition by siRNA blocked the IGF-II-induced MMP-9 activity. We hypothesize that after IGF-II is bound with IGF2R, the resulting signal disrupts the balance in the MMP-9/TIMP-2 expression level and increases plasminogen activator (PAs) expression involved in the development of myocardial remodeling. If so, IGF2R signaling inhibition may have potential use in the development of therapies preventing heart fibrosis progression.

Effects of Age on Plasma Matrix Metalloproteinases (MMPs) and Tissue Inhibitor of Metalloproteinases (TIMPs)

Background The mechanisms causing age-dependent changes in left ventricular (LV) structure and function are not completely understood. Matrix metalloproteinase (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) constitute one important proteolytic pathway affecting LV remodeling. However, whether these determinants of extracellular matrix (ECM) composition change as a function of age has not been examined in an aging population free of clinically significant cardiovascular disease. Methods and Results Subjects (n = 77, age 20–90 years) with no evidence of cardiovascular disease underwent echocardiography and measurement of plasma MMP-2, 7, 8, and 9 and TIMP-1, 2, and 4 (enzyme-linked immunosorbent assay). As subject age increased, volume/mass ratio decreased and mitral E/A ratio decreased. As subject age increased, MMP-2 increased (from 1188 ± 99 ng/mL to 1507 ± 76 ng/mL), MMP-7 increased (from 1.2 ± 0.1 ng/mL to 3.1 ± 0.6 ng/mL), MMP-9 decreased (from 29 ± 7 ng/mL to 8 ± 2 ng/mL), and TIMP-1, 2, and 4 increased (from 728 ± 46 ng/mL to 1093 ± 73 ng/mL, from 34 ± 5 ng/mL to 53 ± 6 ng/mL, and from 1.26 ± 0.22 ng/mL to 2.34 ± 0.30 ng/mL, respectively) (all P < .05). There were significant correlations between decreased LV volume/mass and E/A ratio and increased MMP-7 and TIMP-1 and 4. Conclusions MMPs and TIMPs changed as a function of age in the absence of clinically significant cardiovascular disease. These age-dependent alterations in MMP and TIMP profiles favor ECM accumulation and were associated with concentric remodeling and decreased LV diastolic function. Because of these age-dependent changes in this proteolytic system, the superimposition of disease processes such as myocardial infarction or hypertensive heart disease in the older subject may result in different myocardial ECM remodeling than that seen in a younger subject.

Selective Impairment of Nuclear Factor-κB-Dependent Gene Transcription in Adult Cardiomyocytes

The ability of neonatal and adult cardiomyocytes to activate the nuclear factor (NF)-kappaB pathway in response to lipopolysaccharide and interleukin-1beta challenge has been investigated and compared with that of peritoneal macrophages. The activation of the IkappaB kinase and the phosphorylation and degradation of IkappaBalpha and IkappaBbeta was much lower in adult cardiomyocytes than in the neonatal counterparts and macrophages. This restricted activation of the NF-kappaB pathway resulted in a significant reduction in the time of nuclear activation of NF-kappaB, as deduced by electrophoretic mobility shift assays and in the transcription of target genes, such as IkappaBalpha, cyclooxygenase-2 (COX-2) and nitric-oxide synthase-2 (NOS-2). Studies on chromatin immunoprecipitation showed binding of NF-kappaB proteins to the regulatory kappaB sites identified in the promoters of the IkappaBalpha, COX-2, and NOS-2 genes in macrophages and, to a lower extent, in neonatal cardiomyocytes. The binding to these kappaB sites in adult cardiomyocytes was observed only in the IkappaBalpha promoter and was minimal or absent in the COX-2 and NOS-2 promoters, respectively, suggesting a restricted activation of NF-kappaB-regulated genes in these cells. These data indicate that the function of the NF-kappaB pathway in adult cardiomyocytes is limited in time, which results in the expression of a reduced number of genes and provides a functional explanation for the absence of NOS-2 inducibility in these cells under proinflammatory conditions.

The Effect of Imidaprilat, an ACE Inhibitor on Matrix Metalloproteinase-2 Activity in Human Cardiac Fibroblast

Background: Myocardial extracellular matrix remodeling is regulated by matrix metalloproteinases (MMPs) involving MMP-2. MMP-2 plays an important role in digesting type I, II, and IV collagens. Angiotensin-converting enzyme (ACE) inhibition is used in the treatment of heart failure because of the attenuation of LV remodeling. In this study, we demonstrated that imidaprilat inhibited MMP-2 activity in human cardiac fibroblasts induced by IL-1β via NO-dependent pathway.