Role In Cardiac Remodeling Research Articles

The Relationship Between BigET-1 and Cardiac Remodeling in Patients with Hypertrophic Obstructive Cardiomyopathy.

To explore the relationship between BigET-1 and cardiac remodeling in hypertrophic obstructive cardiomyopathy (HOCM). A retrospective analysis was conducted on the data of 150 HOCM patients in a hospital from September 2021 to August 2023. According to the 2015 American Ultrasound Society's recommended standards for quantifying adult UGG cardiac lumen, left atrial enlargement is defined as having a left atrial diameter greater than 40mm in males and greater than 38mm in females. 150 HOCM patients were divided into a left atrial normal group (n = 97) and a left atrial enlargement group (n = 53). Comprehensive patient data were collected, including BigET-1in plasma, N-Terminalpro-B-TypeNatriureticPeptide (NT-pro-BNP), and High-sensitive C-reactive protein (Hs-CRP), as well as cardiac magnetic resonance imaging (CMR) imaging data. The relationship between BigET-1 levels and cardiac remodeling was analyzed. The two groups had no statistical difference in gender, age, heart rate, dyspnea, angina pectoris, etc. (P > 0.05). The χ2-test showed that patients in the left atrial enlargement group had an increased proportion of atrial fibrillation compared to those in the left atrial normal group (P < 0.05). Non parametric tests showed that the Big ET-1 and NT-pro-BNP in the left atrial enlargement group were significantly higher than those in the left atrial normal group (P < 0.05). The t-test results showed that there were statistical differences in Hs-CRP, left atrial anteroposterior diameter, interventricular septum thickness, and LVEDV between the left atrial enlargement group and the left atrial normal group (P < 0.05). Pearson correlation analysis showed that Big ET-1 was positively correlated withNT-pro-BNP, Hs-CRP, left atrial anteroposterior diameter, and interventricular septum thickness (P < 0.05). The multiple linear regression analysis showed that Big ET-1 was positively correlated with NT-pro-BNP and LADap (P < 0.05). In HOCM patients with atrial enlargement, the Big ET-1 is significantly elevated. Cardiac remodeling is more pronounced, indicating that Big ET-1 plays a role in cardiac remodeling in HOCM patients.

MiR-424/322 attenuates cardiac remodeling by modulating the nuclear factor-activated T-cell 3/furin pathway

BackgroundCardiac remodeling is implicated in numerous physiologic and pathologic conditions, including scar formation, heart failure, and cardiac arrhythmias. Nuclear factor-activated T-cell cytoplasmic (NFATc) is a crucial transcription factor that regulates cardiac remodeling. MicroRNA (miR)-424/322 has pathophysiological roles in the cardiovascular and respiratory systems by modulating hypoxia and inflammatory pathways. The role of miR-424/322 in regulating cardiac remodeling is under investigation. We identified several cardiac hypertrophy and fibrosis-related molecules as putative targets of miR-424/322. We propose that miR-424/322 could have crucial roles in cardiac remodeling by modulating several key molecules for cardiac fibrosis and hypertrophy. MethodsHuman cardiac fibroblasts (HCFs) and a myogenic cell line H9c2 cells were used for in vitro experiments. A murine model of angiotensin II (AngII)-induced cardiac remodeling was used to assess the roles of miR-322 on cardiac hypertrophy and fibrosis in vivo. Immunoblotting, immunofluorescence, real-time polymerase chain reaction and cell proliferation, Sirius Red, and dual-luciferase reporter assays were used to decipher the molecular mechanism. ResultsWe found that miR-322 knockout mice were susceptible to AngII-induced cardiac fibrosis and hypertrophy in vivo. Administration of miR-424/322 inhibitors aggravated AngII-induced overexpression of NFATc3, furin, natriuretic peptides and collagen 1A1 in H9c2 cells and HCFs. miR-424/322 mimics reversed the AngII-induced fibrosis, hypertrophy, and proliferation by targeting NFATc3 and furin in vitro. miR-424/322 could be transactivated by NFATc3. Exogenous miR-322 ameliorated AngII-induced hypertrophy and cardiac fibrosis in vivo. ConclusionsThe NFATc3/miR-424/322/furin axis is crucial for developing cardiac remodeling, and exogenous miR-322 mimics could have therapeutic potential in cardiac remodeling.

Myocardial SGLT2 expression and cardiac remodeling in patients with severe aortic stenosis: the BIO-AS Study

Abstract Background Cardiac remodeling plays a major role in the prognosis of patients with aortic stenosis (AS) and could impact the benefits of aortic valve replacement. Blood and tissue biomarkers have a differential pattern and expression level in patients with AS, which may retain a pathophysiological role in cardiac remodeling and metabolism. However, the data available are limited and contradictory. Aim Our study aimed to evaluate the expression of sodium-glucose cotransporter 2 (SGLT2) gene and protein in patients with severe AS stratified in high gradient (HG) and low flow-low gradient (LF-LG) AS and its association with cardiac functional impairments. Methods Gene expression and protein levels of main biomarkers of cardiac fibrosis (Galectin-3, sST2, Serpin-4, PINP, PICP, Collagen, TGF-b), inflammation (GDF-15, IL-6, NF-kB), oxidative stress (SOD1, SOD2), and cardiac metabolism (NHE, PPAR-a, PPAR-g, GLUT1, and GLUT4) were evaluated in blood samples and heart biopsies of 45 patients with AS. Results Our study showed SGLT2 gene and protein hyper-expression in patients with LF-LG AS, compared to controls and HG AS (p&amp;lt;0.05). These differences remained significant even after adjusting for age, gender, body mass index, history of diabetes mellitus, arterial hypertension, and coronary artery disease. SGLT2 gene expression was positively correlated with: i) TGF-b (r=0.72, p&amp;lt;0.001) and collagen (r=0.73, p&amp;lt;0.001) as markers of fibrosis; ii) NF-kB (r=0.36, p&amp;lt;0.01) and myocardial IL-6 (r=0.68, p&amp;lt;0.001) as markers of inflammation: iii) SOD2 (r=-0.38, p&amp;lt;0.006) as a marker of oxidative stress; iv) GLUT4 (r= 0.33, p&amp;lt;0.02) and PPAR-a (r=0.36, p&amp;lt;0.01) as markers of cardiac metabolism (Figure 1). Conclusion In patients with LF-LG AS, SGLT2 gene and protein were hyper-expressed in cardiomyocytes and associated with myocardial fibrosis, inflammation, and oxidative stress. The hyper-expression of the SGLT2 gene and protein in patients with LF-LG might pave the way for using SGLT2-Is in this subset population, with the potential to improve the outcomes of AVR and reduce the likelihood of re-hospitalization within one year.Figure 1

Interleukin-22 inhibits right ventricular remodelling by a unique mechanism in a pulmonary artery constriction model

Abstract Background Fibrosis and remodeling of right ventricle (RV) are associated with prognosis in patients with RV failure. Interleukin-22 (IL-22) is a member of the IL-10 cytokine family, play roles in tissue protection and wound repair. We have previously shown that IL-22 plays an important role in cardiac remodeling after acute myocardial infarction; however, the role of IL-22 in RV fibrosis and remodeling remains elusive. Purpose We investigated the role of IL-22 in the pathogenesis of RV remodeling during pressure overload. Methods Pulmonary artery banding (PAB) is performed by placing a 6-0 suture around the pulmonary artery over a 24 G needle in wild type mice (C57BL/6J) and IL-22 knockout mice (IL-22 KO). Only mice with moderate pulmonary artery stenosis (peak pressure gradient across the pulmonary band: 25–40 mmHg at 1 week after surgery by echo Doppler) were included in the study protocol. Four weeks after PAB, RV function was measured by echocardiography and real-time PCR analysis was performed to measure Col1a1, Col3a1, BNP, and transcriptome analysis was performed. Survival confirmation of mice with moderate pulmonary artery stenosis was also performed up to 56 days. Results IL-22 KO mice had significantly higher 56-day mortality rate compared with WT mice after PAC (p&amp;lt;0.01). Four weeks after PAB, IL-22 KO mice showed markedly increased RV weight (IL-22 KO mice vs. wild-type mice; RV/LV+IVS: 0.48±0.05 vs 0.40±0.02, P=0.002). IL-22 KO mice exhibited significant RV enlargement and RV dysfunction 4 weeks after PAB. (IL-22 KO mice vs wild type mice; RVEDV: 10±2.3mm2 vs 12.9±3.1mm2, P=0.005, TAPSE: 10.8±1.8mm vs 9.5±1.7mm, P=0.04, FAC: 35.2±7.8% vs 23±6.0%, P&amp;lt;0.001). The expressions of Col1a1 and Col3a1 were no difference between in IL22-KO mice and Wild mice. However, BNP, a cardioprotective marker, tended to be lower in IL-22KO mice. The transcriptome analysis also showed that the group of fibrosis-related genes that are elevated in PAC in WT mice were less elevated in IL-22 KO mice. Conclusion These results suggest that IL-22 is involved in RV remodelling during RV pressure loading without a general mechanism.

The role of IL15 in angiotensin II-mediated cardiac remodelling

Abstract Hypertension (HTN) mediated target organ damage, such as cardiac remodelling, is a major cause of death and disability. Cytokines are important regulators of cardiac function, inflammation, and remodelling in cardiovascular disease. Increased levels of interleukin 15 (IL15) have been noted in HTN, but its role in HTN heart disease remains unknown. This study investigates the role of the IL15 axis in the pathogenesis of cardiac remodelling in HTN. Male 12-week-old IL15 receptor α knock-out (IL15RAKO), IL15 knock-out (IL15KO) and matching wild type (WT) mice were administered vehicle or angiotensin II (AngII) (490 ng/min/kg) for 2 weeks by osmotic minipump. Blood pressure was measured by tail cuff (n=5-8). Cardiac function was analysed by echocardiography (n=3-4). Cardiac infiltrating immune cells were analysed by flow cytometry (n=2-3 for IL15RAKO, n=6-10 for IL15KO). Cardiac remodelling was assessed by picrosirius red, WGA staining (n=5-8) and expression of markers of remodelling using RT-qPCR and western blots (n=5-8). Data are presented as mean±SEM and analysed using two-way ANOVA. AngII infusion caused a significant increase in systolic blood pressure in WT and IL15KO animals. In contrast, in IL15RAKO, the response to AngII was blunted. This was in line with a decrease in ejection fraction, however only WT mice had an increase in global longitudinal strain (-20.3±2.0 vs -10.9±1.2, p=0.0039 in WT and 19.9±0.8 vs -16.0±2.1, p=0.1878 in IL15RAKO). HTN was associated with increased cardiac IL15 protein levels in mice. The heart-to-body ratio, along with cardiomyocyte cross-sectional, were significantly increased in WT, but not in IL15RAKO HTN mice. Furthermore, histological analysis showed significantly higher cardiac collagen accumulation in WT but not IL15RAKO upon AngII infusion (5.8±1.0% in WTvvs. 2.1±0.5% in IL15RAKO, p=0.0021). This was in line with a higher expression of col1a1 in WT but not IL15RAKO HTN hearts (20.0±6.0 vs 4.5±1.7, p=0.0173). Similarly, the FN1 protein level was significantly increased in WT but not IL15RAKO AngII-treated mice. These changes were associated with a higher number of Cd11b+ macrophages accumulated in WT hypertensive hearts only. In contrast to IL15RAKO, mice lacking IL15 showed similar increases in global longitudinal strain, heart hypertrophy, and cardiomyocyte cross-sectional area as WT mice upon AngII infusion. Similarly, IL15KO hypertensive hearts showed a significant increase of col1a1 and FN1 in comparison to vehicle-treated mice. A similar level of Cd11b+ macrophages was found in hypertensive IL15KO and WT mice's hearts. In conclusion, IL15RA, but not IL15, plays a critical role in cardiac remodelling mediated by AngII infusion. This suggests that the IL15-IL15RA axis may play an important yet complex role in hypertensive heart disease.

Immunohistochemical Localization of Fibroblast Activation Protein in Coronary Arteries with Different Forms of Atherosclerosis.

Background: Fibroblast activation protein (FAP) is a cell surface glycoprotein expressed by myofibroblasts in areas of active tissue remodeling. It plays a potentially important role in cardiac remodeling, atherosclerotic plaque formation, and plaque rupture. Given the distinct pathophysiology and morphology of different forms of atherosclerosis, we analyzed FAP expression in human coronary vessels with no coronary artery disease, atherosclerotic plaques at different levels of progression, and other distinct forms of coronary disease in post bypass vein grafting and cardiac allograft vasculopathy after a heart transplant. Methods: Immunohistochemical staining with monoclonal F19 mouse anti-human FAP antibody was performed to identify FAP in human atherosclerotic plaques, coronary bypass atherosclerosis, and post-transplant arteriosclerosis. The presence and distribution of FAP in different types and stages of human atherosclerosis were compared. Results: There was no FAP staining in patients with no significant coronary disease. All different types of human atherosclerotic lesioning lesions showed the presence of FAP expression, with different staining patterns in advanced atherosclerotic plaque, vein graft atherosclerosis lesions, and arteriosclerosis after a heart transplant. Conclusions: These data suggest that FAP may be a potential diagnostic marker and target for interventions, not only in coronary atherosclerotic plaque, but also in other forms of coronary disease, which have distinct pathophysiologies and currently limited treatment options.

Aerobic Exercise Improved Diacylglycerol/Protein Kinase C and Phosphatidylinositol 4,5-Biphosphate Pathway in Cardiac Tissue of Obese Rats

Background: Obesity, characterized by abnormal accumulation or excess lipids, is a major cause of increased incidence of cardiovascular diseases. Objectives: The purpose of this experiment is to investigate the effect of aerobic exercise on the expression of sn-1,2-diacylglycerol (DAG), Protein kinase C (PKC), and Phosphatidylinositol 4,5-biphosphate (PIP2) genes in experimental rat models of diet-induced obesity. Methods: Twenty-four Wistar rats were randomly divided into four groups: (1) control, (2) obesity, (3) exercise, and (4) obesity + exercise. At the end of the experiment, cardiac hypertrophy markers and real-time PCR were used to evaluate and compare the gene expression levels of DAG, PKC, and PIP2 in cardiac tissue across all groups. Results: A high-fat diet containing fructose significantly increased the gene expression levels of DAG, PKC, and PIP2 in the cardiac tissue of obese rats compared to the control group. However, 6 weeks of aerobic exercise led to a significant decrease in DAG and PKC gene expression compared to the obese rats. Although there was no significant change in PIP2 gene expression in the obesity + exercise group compared to obese rats. Conclusions: Based on the results of this study, it appears that aerobic exercise can modulate the expression of DAG and PKC genes, which play a critical role in cardiac remodeling.

GQ262 Attenuates Pathological Cardiac Remodeling by Downregulating the Akt/mTOR Signaling Pathway.

Cardiac remodeling, a critical process that can lead to heart failure, is primarily characterized by cardiac hypertrophy. Studies have shown that transgenic mice with Gαq receptor blockade exhibit reduced hypertrophy under induced pressure overload. GQ262, a novel Gαq/11 inhibitor, has demonstrated good biocompatibility and specific inhibitory effects on Gαq/11 compared to other inhibitors. However, its role in cardiac remodeling remains unclear. This study aims to explore the anti-cardiac remodeling effects and mechanisms of GQ262 both in vitro and in vivo, providing data and theoretical support for its potential use in treating cardiac remodeling diseases. Cardiac hypertrophy was induced in mice via transverse aortic constriction (TAC) for 4 weeks and in H9C2 cells through phenylephrine (PE) induction, confirmed with WGA and H&E staining. We found that GQ262 improved cardiac function, inhibited the protein and mRNA expression of hypertrophy markers, and reduced the levels of apoptosis and fibrosis. Furthermore, GQ262 inhibited the Akt/mTOR signaling pathway activation induced by TAC or PE, with its therapeutic effects disappearing upon the addition of the Akt inhibitor ARQ092. These findings reveal that GQ262 inhibits cardiomyocyte hypertrophy and apoptosis through the Akt/mTOR signaling pathway, thereby reducing fibrosis levels and mitigating cardiac remodeling.

O17 THE PROGRESSION OF HYPERTENSION WITH OBESITY AND DIABETES FAVORS CARDIAC PRO-INFLAMMATORY MACROPHAGES AND DIASTOLIC DYSFUNCTION

Background: In most patients, hypertension (HT) is accompanied by obesity and diabetes. Cell-specific mechanisms like accumulation of macrophages, and dysregulation of innate immune pathways play important roles in cardiac remodeling (CR). Macrophages (Mo) exhibit phenotypic heterogeneity in response to tissue micro-environment. It is unknown whether in the heart the subpopulations of pro-inflammatory Mo (CCR2+MHCII+) and resident repair Mo (CCR2-MHCII+ and CCR2-MHCII-) differ in the development of the chronic HT, obesity and diabetes. Objective. To determine in male with HT and or obesity and diabetes, the pro-inflammatory cardiac Mo derived from monocytes (CCR2+MHCII+) and the resident repair Mo (CCR2-MHCII+ and CCR2- MHCII-). Methods: 12-week-old male C57BL/6N mice were assigned to experimental groups: control diet, high-fat diet (HFD, 60% kcal from fat), L-NAME (L,0.65 g/L in drinking water) and HFD+L for 5 and 15 weeks. Body weight (BW), systolic (SBP) and diastolic blood pressure, glucose and exercise capacity (EC), cardiac function and cardiac Mo CCR2+MHCII+, CCR2-MHCII+, CCR2- MHCII- were determined. Results: (mean ± SEM, n=9-12). During 15 weeks, HFD and HFD+L groups showed significantly higher BW and glucose intolerance vs. control and L (p &lt;0.001, F=28.4; p&lt;0.001, F=10.3, respectively). EC as lower in the HFD and HFD+L groups compared to control and L (p&lt;0.059). Echocardiographic parameters showed a significant increase in the size of the left atrium (p&lt;0.001, F=38.9) and diastolic dysfunction in the HFD+L group vs control, HFD and L (p&lt;0.001, F=35.6). No changes in ejection fraction and shortening fraction. The thickness of the septal wall and posterior wall was significantly greater in the HFD+L and HFD groups (p&lt;0.0001, F=10.6 and p&lt;0.0001, F=14.6, respectively). The L hearts showed a significant increase in CCR2-MHCII- (p&lt;0.0001, F=68.6) and a significant decrease in CCR2+ MHCII+ (p&lt;0.001, F=13.7), compared to the control and HFD groups. Conclusion: The progression of HT with obesity and diabetes favors cardiac pro-inflammatory macrophages and diastolic dysfunction.

SGK3 deficiency in macrophages suppresses angiotensin II–induced cardiac remodeling via regulating Ndufa13–mediated mitochondrial oxidative stress

Infiltration of monocyte-derived macrophages plays a crucial role in cardiac remodeling and dysfunction. The serum and glucocorticoid-inducible protein kinase 3 (SGK3) is a downstream factor of PI3K signaling, regulating various biological processes via an AKT-independent signaling pathway. SGK3 has been implicated in cardiac remodeling. However, the contribution of macrophagic SGK3 to hypertensive cardiac remodeling remains unclear. A cardiac remodeling model was established by angiotensin II (Ang II) infusion in SGK3-Lyz2-CRE (f/f, +) and wild-type mice to assess the function of macrophagic SGK3. Additionally, a co-culture system of SGK3-deficient or wild-type macrophages and neonatal rat cardiomyocytes (CMs) or neonatal rat fibroblasts (CFs) was established to evaluate the effects of SGK3 and the underlying mechanisms. SGK3 levels were significantly elevated in both peripheral blood mononuclear cells and serum from patients with heart failure. Macrophage SGK3 deficiency attenuated Ang II–induced macrophage infiltration, myocardial hypertrophy, myocardial fibrosis, and mitochondrial oxidative stress. RNA sequencing suggested Ndufa13 as the candidate gene in the effect of SGK3 on Ang II–induced cardiac remolding. Downregulation of Ndufa13 in CMs and CFs prevented the suppression of cardiac remodeling caused by SGK3 deficiency in macrophages. Mechanistically, the absence of SGK3 led to a reduction in IL-1β secretion by inhibiting the NLRP3/Caspase-1/IL-1β pathway in macrophages, consequently suppressing upregulated Ndufa13 expression and mitochondrial oxidative stress in CMs and CFs. This study provides new evidence that SGK3 is a potent contributor to the pathogenesis of hypertensive cardiac remodeling, and targeting SGK3 in macrophages may serve as a potential therapy for cardiac remodeling.

Abstract Tu041: Gut microbiome Bifidobacterium is associated with improvement in severity of heart failure with reduced ejection fraction

Background: Heart failure (HF) has been associated with dysregulated gut microbiome. However, less is understood about how gut microbiome alterations relate to changes in HF severity. We sought to understand how gut microbial shifts and associated host signatures related to changes in clinical status of patients with HF with reduced ejection fraction (HFrEF). Methods: Twenty-six adults with HFrEF were recruited and completed 2 study visits approximately 6 months apart. At each visit they provided stool sample for microbiome profiling (metagenomic sequencing), and fasting blood samples for untargeted metabolomics (liquid chromatography–mass spectrometry) and cytokine assay (Luminex antibody-conjugated bead capture). Subjects also completed dietary surveys. Clinical improvement was measured as between-visit change in the New York Heart Association (NYHA) class. Results: Between-visit NYHA class improved in 6 individuals; 20 patients remained stable or worsened. After accounting for demographics, body mass index, and diet, genus Bifidobacterium was significantly enriched in the improved group and increased over time (Figure 1). Bifidobacterium was directly associated with circulating malonic acid, which is implicated in cardio-protection and cardiomyocyte regeneration, and with indole-3-propionate (IPA), anti-inflammatory gut microbial metabolite of dietary tryptophan (Figure 2). There was also a positive correlation between Bifidobacterium and IL10, a major anti-inflammatory cytokine that plays a role in cardiac remodeling. Conclusion: Bifidobacterium was independently associated with longitudinal improvement in functional status in patients with HFrEF. Additionally, Bifidobacterium correlated with circulating IPA, malonic acid, and IL10. Our findings support (1) gut Bifidobacterium as a potential biomarker of clinical improvement in HFrEF and a possible new therapeutic target, and (2) potential downstream mediators through which Bifidobacterium may regulate HF pathophysiology.

Low levels of supercoiled mitochondrial DNA are involved in heart failure induced by transverse aortic constriction in mice via an inflammatory response mediated by ZBP1

BackgroundInflammation in the myocardium plays a critical role in cardiac remodeling and the pathophysiology of heart failure (HF). Previous studies have shown that mitochondrial DNA (mtDNA) can exist in different topological forms. However, the specific influence of the ratio of supercoiled/relaxed mtDNA on the inflammatory response in cardiomyocytes remains poorly understood. The aim of this study was to elucidate the differential effects of different mtDNA types on cardiomyocyte inflammation through regulation of ZBP1. Materials and methodsA mouse model of HF was established by transverse aortic constriction (TAC) or doxorubicin (Doxo) induction. Histopathological changes were assessed by HE staining. ELISA was used to measure cytokine levels (IL-1β and IL-6). Southern blot analysis was performed to examine the different topology of mtDNA. Pearson correlation analysis was used to determine the correlation between the ratio of supercoiled/relaxed mtDNA and inflammatory cytokines. Reverse transcription quantitative PCR (RT-qPCR) was used to measure the mRNA expression levels of cytokines (IL-1β, IL-6) and Dloop, as an mtDNA marker. ResultsThe ratio of supercoiled to relaxed mtDNA was significantly increased in the myocardium of Doxo-induced mice, whereas no significant changes were observed in TAC-induced mice. The levels of IL-1β and IL-6 were positively correlated with the cytoplasmic mtDNA supercoiled/relaxed circle ratio. Different mtDNA topology has different effects on inflammatory pathways. Low supercoiled mtDNA primarily activates the NF-κB (Ser536) pathway via ZBP1, whereas high supercoiled mtDNA significantly affects the STAT1 and STAT2 pathways. The RIPK3-NF-κB pathway, as a downstream target of ZBP1, mediates the inflammatory response induced by low supercoiled mtDNA. Knockdown of TLR9 enhances the expression of ZBP1, p-NF-κB, and RIPK3 in cardiomyocytes treated with low supercoiled mtDNA, indicating the involvement of TLR9 in the anti-inflammatory role of ZBP1 in low supercoiled mtDNA-induced inflammation. ConclusionDifferent ratios of supercoiled to relaxed mtDNA influence the inflammatory response of cardiomyocytes and contribute to HF through the involvement of ZBP1. ZBP1, together with its downstream inflammatory mechanisms, mediates the inflammatory response induced by a low ratio of supercoiled mtDNA.

Understanding Galectin-3's Role in Diastolic Dysfunction: A Contemporary Perspective.

Diastolic dysfunction, a prevalent condition characterized by impaired relaxation and filling of the left ventricle, significantly contributes to heart failure with preserved ejection fraction (HFpEF). Galectin-3, a β-galactoside-binding lectin, has garnered attention as a potential biomarker and mediator of fibrosis and inflammation in cardiovascular diseases. This comprehensive review investigates the impact of galectin-3 on diastolic dysfunction. We explore its molecular mechanisms, including its involvement in cellular signaling pathways and interaction with components of the extracellular matrix. Evidence from both animal models and clinical studies elucidates galectin-3's role in cardiac remodeling, inflammation, and fibrosis, shedding light on the underlying pathophysiology of diastolic dysfunction. Additionally, we examine the diagnostic and therapeutic implications of galectin-3 in diastolic dysfunction, emphasizing its potential as both a biomarker and a therapeutic target. This review underscores the significance of comprehending galectin-3's role in diastolic dysfunction and its promise in enhancing diagnosis and treatment approaches for HFpEF patients.

Compound 3K attenuates isoproterenol-induced cardiac hypertrophy by inhibiting pyruvate kinase M2 (PKM2) pathway

AimChronic sympathetic stimulation has been identified as a primary factor in the pathogenesis of cardiac hypertrophy (CH). However, there is no appropriate treatment available for the management of CH. Recently, it has been revealed that pyruvate kinase M2 (PKM2) plays a significant role in cardiac remodeling, fibrosis, and hypertrophy. However, the therapeutic potential of selective PKM2 inhibitor has not yet been explored in cardiac hypertrophy. Thus, in the current study, we have studied the cardioprotective potential of Compound 3K, a selective PKM2 inhibitor in isoproterenol-induced CH model. MethodsTo induce cardiac hypertrophy, male Wistar rats were subcutaneously administered isoproterenol (ISO, 5 mg/kg/day) for 14 days. Compound 3K at dosages of 2 and 4 mg/kg orally was administered to ISO-treated rats for 14 days to explore its effects on various parameters like ECG, ventricular functions, hypertrophic markers, histology, inflammation, and protein expression were performed. ResultsFourteen days administration of ISO resulted in the induction of CH, which was evidenced by alterations in ECG, ventricular dysfunctions, increase in hypertrophy markers, and fibrosis. The immunoblotting of hypertrophy heart revealed the significant rise in PKM2 and reduction in PKM1 protein expression. Treatment with Compound 3K led to downregulation of PKM2 and upregulation of PKM1 protein expression. Compound 3K showed cardioprotective effects by improving ECG, cardiac functions, hypertrophy markers, inflammation, and fibrosis. Further, it also reduced cardiac expression of PKM2-associated splicing protein, HIF-1α, and caspase-3. ConclusionOur findings suggest that Compound 3K has a potential cardioprotective effect via PKM2 inhibition in isoproterenol-induced CH.

Striatin plays a major role in angiotensin II-induced cardiomyocyte and cardiac hypertrophy in mice in vivo.

The three striatins (STRN, STRN3, STRN4) form the core of STRiatin-Interacting Phosphatase and Kinase (STRIPAK) complexes. These place protein phosphatase 2A (PP2A) in proximity to protein kinases thereby restraining kinase activity and regulating key cellular processes. Our aim was to establish if striatins play a significant role in cardiac remodelling associated with cardiac hypertrophy and heart failure. All striatins were expressed in control human hearts, with up-regulation of STRN and STRN3 in failing hearts. We used mice with global heterozygote gene deletion to assess the roles of STRN and STRN3 in cardiac remodelling induced by angiotensin II (AngII; 7 days). Using echocardiography, we detected no differences in baseline cardiac function or dimensions in STRN+/- or STRN3+/- male mice (8 weeks) compared with wild-type littermates. Heterozygous gene deletion did not affect cardiac function in mice treated with AngII, but the increase in left ventricle mass induced by AngII was inhibited in STRN+/- (but not STRN3+/-) mice. Histological staining indicated that cardiomyocyte hypertrophy was inhibited. To assess the role of STRN in cardiomyocytes, we converted the STRN knockout line for inducible cardiomyocyte-specific gene deletion. There was no effect of cardiomyocyte STRN knockout on cardiac function or dimensions, but the increase in left ventricle mass induced by AngII was inhibited. This resulted from inhibition of cardiomyocyte hypertrophy and cardiac fibrosis. The data indicate that cardiomyocyte striatin is required for early remodelling of the heart by AngII and identify the striatin-based STRIPAK system as a signalling paradigm in the development of pathological cardiac hypertrophy.

Reprogramming cardiac macrophages with circular RNAs to attenuate post-MI adverse remodeling

Cardiac macrophages (cMφ) play a critical role in cardiac remodeling following myocardial infarction (MI). Reprogramming cMφ towards a favorable wound-healing phenotype is emerging as a promising therapeutic strategy for MI patients. Circular RNAs (circRNAs) are a unique class of non-coding RNAs with high stability and abundance, making them attractive therapeutic targets. However, the role of circRNAs in cMφ physiology during heart failure (HF) progression is poorly understood. To identify circRNAs as key regulators of cMφ dynamics, we performed RNA sequencing and bioinformatics analysis on heart biopsies from healthy donors and patients with ischemic HF. We identified a promising circRNA, circMJ1, as a regulator of Mφ polarization and inflammatory response. CircMJ1 was highly expressed in cMφ and its expression was associated with cMφ polarization. Knockdown of circMJ1 significantly inhibited inflammatory signaling pathways in cMφ and reduced the secretion of pro-inflammatory cytokines. The secretome from circMJ1-silenced cMφ (circMJ1-KD cMφ) also significantly suppressed the migration of cardiac fibroblasts and apoptosis of cardiomyocytes. To further assess the therapeutic effcacy of circMJ1-KD Mφ in cardiac remodeling in the context of MI, we employed a novel multicellular 3D ex vivo model, called living myocardial slices (LMS). We applied circMJ1-KD Mφ to both rat LMS subjected to cryo-injury mimicking MI and HF patient-derived LMS. Interestingly, co-culture with circMJ1-KD Mφ demonstrated a remarkable reduction in inflammation and fibrosis, alongside notable improvement in cardiac function in both cryo-injured rat LMS and HF patient-derived LMS. Overall, our findings reveal circMJ1 as a crucial "switch" for Mφ dynamics and suggest the therapeutic potential of engineered circMJ1-silenced Mφ to improve post-MI healing. Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) –465131031. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

SIRT3 regulates cardiolipin biosynthesis in pressure overload-induced cardiac remodeling by PPARγ-mediated mechanism.

Cardiac remodeling is the primary pathological feature of chronic heart failure (HF). Exploring the characteristics of cardiac remodeling in the very early stages of HF and identifying targets for intervention are essential for discovering novel mechanisms and therapeutic strategies. Silent mating type information regulation 2 homolog 3 (SIRT3), as a major mitochondrial nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, is required for mitochondrial metabolism. However, whether SIRT3 plays a role in cardiac remodeling by regulating the biosynthesis of mitochondrial cardiolipin (CL) is unknown. In this study, we induced pressure overload in wild-type (WT) and SIRT3 knockout (SIRT3-/-) mice via transverse aortic constriction (TAC). Compared with WT mouse hearts, the hearts of SIRT3-/- mice exhibited more-pronounced cardiac remodeling and fibrosis, greater reactive oxygen species (ROS) production, decreased mitochondrial-membrane potential (ΔΨm), and abnormal mitochondrial morphology after TAC. Furthermore, SIRT3 deletion aggravated TAC-induced decrease in total CL content, which might be associated with the downregulation of the CL synthesis related enzymes cardiolipin synthase 1 (CRLS1) and phospholipid-lysophospholipid transacylase (TAFAZZIN). In our in vitro experiments, SIRT3 overexpression prevented angiotensin II (AngII)- induced aberrant mitochondrial function, CL biosynthesis disorder, and peroxisome proliferator-activated receptor gamma (PPARγ) downregulation in cardiomyocytes; meanwhile, SIRT3 knockdown exacerbated these effects. Moreover, the addition of GW9662, a PPARγ antagonist, partially counteracted the beneficial effects of SIRT3 overexpression. In conclusion, SIRT3 regulated PPARγ-mediated CL biosynthesis, maintained the structure and function of mitochondria, and thereby protected the myocardium against cardiac remodeling.

The association of plasma connective tissue growth factor levels with left ventricular diastolic dysfunction in patients with overt hyperthyroidism.

Left ventricular (LV) diastolic dysfunction is an independent predictor of future cardiovascular events. Early detection of patients with LV diastolic dysfunction can improve clinical outcomes through active management. However, the assessment of diastolic function is very complicated, and there are currently lack of effective biomarkers to assess the risk of LV diastolic dysfunction. Connective tissue growth factor (CTGF) plays a significant role in cardiac remodeling and dysfunction. We aimed to investigate the associations between plasma CTGF level and the risk of LV diastolic dysfunction in this study and judge its effectiveness in diagnosing LV diastolic dysfunction. A total of 169 patients with overt hyperthyroidism were included. LV diastolic function was evaluated and the subjects were divided into normal LV diastolic function group and LV diastolic dysfunction group. Routine clinical medical data, biochemical data, thyroid related parameters and echocardiographic parameters were recorded for analysis. Compared with normal LV diastolic function group, the LV diastolic dysfunction group had higher age and BMI, as well as lower heart rate, lower serum albumin, lower eGFR, higher serum TgAb and BNP level, and the incidences of hypertension were also higher (all P <0.05). Circulating plasma CTGF levels in the LV diastolic dysfunction group were significantly higher (normal LV diastolic function group: 7.026 [5.567-8.895], LV diastolic dysfunction group: 8.290 [7.054-9.225] ng/ml, median [(Interquartile range)], P = 0.004); Compared with the lowest quartile group, the crude odds ratios (OR) of LV diastolic dysfunction in the second, third, and fourth quartile group were 3.207, 5.032 and 4.554, respectively (all P<0.05). After adjustment for the potentially confounding variables, the adjusted OR values of the third and fourth quartile group had no obvious change. The results of ROC showed that the plasma CTGF had the largest area under the ROC curve, and the value was 0.659 (P = 0.005). The level of circulating plasma CTGF in the LV diastolic dysfunction group was significantly increased. Plasma CTGF level is an independent risk factor for LV diastolic dysfunction. Compared with serum BNP level, the plasma CTGF level may have auxiliary diagnostic value for LV diastolic dysfunction in hyperthyroid patients.

TRPV4 Channels Promote Pathological, but Not Physiological, Cardiac Remodeling through the Activation of Calcineurin/NFAT and TRPC6.

TRPV4 channels, which respond to mechanical activation by permeating Ca2+ into the cell, may play a pivotal role in cardiac remodeling during cardiac overload. Our study aimed to investigate TRPV4 involvement in pathological and physiological remodeling through Ca2+-dependent signaling. TRPV4 expression was assessed in heart failure (HF) models, induced by isoproterenol infusion or transverse aortic constriction, and in exercise-induced adaptive remodeling models. The impact of genetic TRPV4 inhibition on HF was studied by echocardiography, histology, gene and protein analysis, arrhythmia inducibility, Ca2+ dynamics, calcineurin (CN) activity, and NFAT nuclear translocation. TRPV4 expression exclusively increased in HF models, strongly correlating with fibrosis. Isoproterenol-administered transgenic TRPV4-/- mice did not exhibit HF features. Cardiac fibroblasts (CFb) from TRPV4+/+ animals, compared to TRPV4-/-, displayed significant TRPV4 overexpression, elevated Ca2+ influx, and enhanced CN/NFATc3 pathway activation. TRPC6 expression paralleled that of TRPV4 in all models, with no increase in TRPV4-/- mice. In cultured CFb, the activation of TRPV4 by GSK1016790A increased TRPC6 expression, which led to enhanced CN/NFATc3 activation through synergistic action of both channels. In conclusion, TRPV4 channels contribute to pathological remodeling by promoting fibrosis and inducing TRPC6 upregulation through the activation of Ca2+-dependent CN/NFATc3 signaling. These results pose TRPV4 as a primary mediator of the pathological response.

Can Glypican-6 Levels Be Used to Determine Right Ventricular Remodeling After Non-ST Segment Elevation Myocardial Infarction?

Myocardial infarction is associated with right ventricular (RV) remodeling. Glypican-6 (GPC6), a member of the membrane proteoglycan family, plays a significant role in cardiac remodeling. This study aims to determine if GPC6 can predict RV remodeling after percutaneous coronary intervention (PCI) in patients with non-ST segment elevation myocardial infarction (NSTEMI). The study enrolled 164 consecutive patients with NSTEMI and controls. It compared baseline plasma GPC6 levels, echocardiography, and laboratory parameters between the RV remodeling and non-RV remodeling groups with NSTEMI. Echocardiographic data were measured at baseline and at six months. GPC6 levels were higher in the NSTEMI group 11.06 ng/mL (4.61-18.17) vs. 5.98 ng/mL (3.81-9.83) compared to the control group in the initial phase. RV remodeling, defined as a ≥ 20% increase in RV end-diastolic area (RV EDA), was observed in 23 patients (30%). After six months, RV EDA increased significantly from baseline 18.68 ± 1.20 cm2 vs. 24.91 ± 1.08 cm2, P < 0.001. GPC6 was a significant independent predictor of RV remodeling (hazard ratio [HR]: 1.546, 95% confidence interval [CI]: 1.056-2.245, P < 0.001). Receiver operating characteristic curve (ROC) analyses showed that GPC6 values > 15.5 ng/mL (area under the curve [AUC] = 0.828, sensitivity: 70%, specificity: 74%, P < 0.001) were strong predictors of RV remodeling. NSTEMI patients should be closely monitored for RV remodeling. GPC6 appears useful in detecting RV remodeling following NSTEMI in patients undergoing PCI.