Septic Myocardial Dysfunction Research Articles

Sepsis induces the cardiomyocyte apoptosis and cardiac dysfunction through activation of YAP1/Serpine1/caspase-3 pathway.

Sepsis triggers myocardial injury and dysfunction, leading to a high mortality rate in patients. Cardiomyocyte apoptosis plays a positive regulatory role in septic myocardial injury and dysfunction. However, the mechanism is unclear. Bioinformatics analysis was used to identify differentially expressed genes in septic mice heart and validate key genes and pathways. The correlation of protein-protein and protein-pathway was analyzed. Sequentially, the cecal ligament and puncture (CLP) was used to induce septic mice, followed by Serpine1 inhibitor treatment. Finally, the regulatory relationship of Yes-associated protein1 (YAP1), Serpine1, and caspase-3 was verified in LPS-exposed mouse cardiomyocytes. Bioinformatic analysis found that Serpine1 expression is decreased in septic mice heart tissue and closely related to the HIPPO signaling pathway, while YAP1 is negatively correlated with apoptosis. In vivo, CLP induced a reduction of survival rate, cardiac dysfunction, and an increase in Serpine1 and Cleaved Caspase-3 expression, which could be reversed by a Serpine1 inhibitor. In vitro, LPS induced the mouse cardiomyocytes apoptosis, which could be reversed by Serpine1 inhibitor. Silencing YAP1 and Serpine1 reversed the LPS-induced increase in Serpine1 and Cleaved Caspase-3 expression, but silencing Serpine1 did not affect the LPS-induced YAP1 expression. Sepsis induced mouse cardiomyocytes apoptosis and cardiac dysfunction through activation of YAP1/Serpine1/caspase-3 pathway.

Hemodynamic assessment and management of septic shock in children

Abstract The three main pathophysiologic contributors to septic shock include varying combinations of hypovolemia (relative > absolute), vasoplegia, and myocardial dysfunction. The three pillars of hemodynamic support include fluid boluses (FBs), vasopressors ± inotropic agents. The three goals of hemodynamic resuscitation include an adequate cardiac output (CO)/clinical perfusion markers, pressure parameters (adequate mean arterial pressure [MAP] and diastolic blood pressure [DBP]) for organ perfusion, and avoiding congestion (worse filling) parameters. Fluid bolus-induced CO improvements are variable (33%–50%) and ill-sustained on account of sepsis-mediated glycocalyx injury. A pragmatic approach is to administer a small bolus (10 mL/kg over 20–30 min) as a test and judge the response based on clinical perfusion markers, pressure parameters, and congestive features. Vasoplegia is characterized by low DBP, which is a major contributor to hypotension in septic shock; furthermore, FBs may exacerbate vasoplegia. A strategy of restricted FB with early low-dose norepinephrine (NE) (0.05–0.1 µg/kg/min) can be helpful. NE has press or effects and also mild inotropy and can be a useful first-line vasoactive even in patients with mild-moderate septic myocardial dysfunction (SMD) to maintain adequate coronary perfusion and DBP while minimizing tachycardia. Severe SMD may benefit from additional inotropy (epinephrine/dobutamine). Except vasopressin, most vasoactive drugs may safely be administered via a peripheral route. The lowest MAP (5th centile for age) may be an acceptable target, provided that end-organ perfusion and organ function (mentation and urine output) are satisfactory. An individualized rather than protocolized approach combining the history, physical examination, laboratory analyses, available monitoring tools, and re-assessments can improve outcomes.

Integration of transcriptomic, proteomic, and metabolomic data to identify lncRNA rPvt1 associations in lipopolysaccharide-treated H9C2 cardiomyocytes

Background: Recent evidence has shown that the long non-coding RNA (lncRNA) rPvt1 is elevated in septic myocardial tissues and that its knockdown attenuates sepsis-induced myocardial injury. However, the mechanism underlying the role of rPvt1 in septic myocardial dysfunction has not been elucidated.Methods: In this study, we performed transcriptomic, proteomic, and metabolomic assays and conducted an integrated multi-omics analysis to explore the association between rPvt1 and lipopolysaccharide (Lipopolysaccharide)-induced H9C2 cardiomyocyte injury. LncRNA rPvt1 silencing was achieved using a lentiviral transduction system.Results: Compared to those with the negative control, rPvt1 knockdown led to large changes in the transcriptome, proteome, and metabolome. Specifically, 2,385 differentially expressed genes (DEGs), 272 differentially abundant proteins and 75 differentially expressed metabolites (DEMs) were identified through each omics analysis, respectively. Gene Ontology functional annotation, Kyoto Encyclopedia of Genes and Genomes, Nr, eukaryotic orthologous groups, and Clusters of Orthologous Groups of Proteins pathway analyses were performed on these differentially expressed/abundant factors. The results suggested that mitochondrial energy metabolism might be closely related to the mechanism through which Pvt1 functions.Conclusion: These genes, proteins, metabolites, and their related dysregulated pathways could thus be promising targets for studies investigating the rPvt1-regluatory mechanisms involved in septic myocardial dysfunction, which is important for formulating novel strategies for the prevention, diagnosis and treatment of septic myocardial injury.

CircROCK1 Promotes septic myocardial injury through regulating miR-96-5p/OXSR1 axis.

A recent high-throughput sequencing showed that circular RNA Rho-associated kinase 1 (circROCK1) is abnormally highly expressed in sepsis, but whether it is involved in sepsis development remains unclear. The objective of this study was to investigate the biological function of circROCK1 in sepsis-induced myocardial injury and reveal its potential downstream molecular mechanism. Real-time reverse transcriptase-polymerase chain reaction was applied to detect circROCK1 and miR-96-5p expressions in the serum of septic patients. Spearman correlation analysis examined the correlation between circROCK1 and the clinicopathological characteristics of septic patients. The Cecal puncture and ligation (CLP) method was used to establish an in vivo sepsis model. circROCK1 and miR-96-5p expressions in mice were modified by injection of lentivirus or oligonucleotide. The left ventricular systolic pressure, left ventricular end-diastolic pressure, and the maximum increase/decrease rate of left ventricular pressure were checked. ELISA was applied to detect inflammatory factors levels as well as myocardial injury markers levels. Hematoxylin and eosin staining was performed to observe pathological changes in myocardial tissues, and Western blot examined phosphorylated nuclear factor (NF)-κB and oxidative stress-responsive 1 (OXSR1) expression. Dual luciferase reporter experiment was conducted to confirm the targeting relationship between circROCK1, OXSR1, and miR-96-5p. circROCK1 and OXSR1 were highly expressed in sepsis and miR-96-5p was under-expressed. circROCK1 was positively correlated with serum creatinine, C-reactive protein, procalcitonin, and sequential organ failure assessment scores in septic patients. Silencing circROCK1 could improve the diastolic and systolic function of CLP mice, as well as myocardial damage, reduce myocardial tissue edema and necrosis, and inhibit inflammatory factor level and phosphorylated NF-κB expression. Down-regulating miR-96-5p promoted myocardial injury in CLP mice. Silencing circROCK1 and miR-96-5p inhibited and promoted OXSR1 expression, respectively. Both circROCK1 and OXSR1 had a targeting relationship with miR-96-5p. CircROCK1 promotes myocardial injury in septic mice by regulating the miR-96-5p/OXSR1 axis, and it can be used as a potential target for treating septic myocardial dysfunction.

Research progress of traditional Chinese and western medicine on myocardial dysfunction in sepsis

Sepsis is a dangerous disease with high mortality, which brings a huge economic burden to patients and society and has attracted more and more attention from the society. Sepsis is a systemic infectious disease. The dysregulated host immune response caused by infection is easy to cause multiple organ damage, and the heart is one of the most vulnerable organs, which leads to septic myocardial dysfunction. Therefore, the treatment of sepsis-induced myocardial dysfunction is a difficult and important point. In recent years, traditional Chinese medicine has shown great advantages in the treatment of this disease. Through the combination of disease differentiation and syndrome differentiation, the overall treatment rate can be significantly improved. Therefore, it is a bright prospect for the treatment of sepsis myocardial dysfunction with integrated traditional Chinese and western medicine. In recent years, the combination of traditional Chinese medicine and western medicine has made some progress in the treatment of sepsis, which has significantly reduced the mortality of sepsis.

MiR-155 protects against sepsis-induced cardiomyocyte apoptosis via activation of NO/cGMP signaling pathway by eNOS

Purpose: To examine the impact of miR-155 on sepsis-induced myocardial apoptosis and heart failure, and to explore its molecular mechanism.
 Methods: Mice were divided into four groups and septic myocardial dysfunction was induced by intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg). The LPS stimulation expression of miR-155 levels was determined by real time-polymerase chain reaction (RT-PCR). In vivo, echocardiography and TUNEL staining were used to investigate the effects of miR-155 in inhibiting cardiac function and myocardial apoptosis. Changes in the expression of eNOS when miR-155 was overexpressed or inhibited were determined by RT-PCR, while double luciferase gene assay assessed the relationship between eNOS and miR-155, eNOS, expression of iNOS, SGC alpha 1, and PKG protein.
 Results: MiR-155 was significantly increased after LPS stimulation (p < 0.01). In vitro, the inhibition of miR-155 by antagomiR significantly down-regulated the apoptosis of cardiomyocytes (p < 0.05), while overexpression of miR-155 by agomiR significantly up-regulated the apoptosis of cardiomyocytes (p < 0.05). In vivo, ejection fraction, fractional shortening and heart weight were significantly increased (p < 0.05), while apoptosis was significantly decreased (p < 0.05). MiR-155 negatively regulated the expression of eNOS (p < 0.01), and targeted the expression of eNOS mRNA (p < 0.001). In addition, the expression of eNOS, sGCα1 and PKA were significantly up-regulated (p < 0.05), while the expression of iNOS was significantly down-regulated (p < 0.05) after the inhibition of miR-155 in LPS mouse model.
 Conclusion: MiR-155 regulates sepsis-induced cardiomyocyte apoptosis and heart failure through eNOS /NO/cGMP signaling pathway. Thus, these findings can potentially facilitate the development of an effective strategy for management of heart failure.

The crosstalk between lipopolysaccharide-induced septic myocardial dysfunction and cardiac lipotoxicity: Toll like receptor 4 as common target of the novel cardioprotective peptide cateslytin

The crosstalk between lipopolysaccharide-induced septic myocardial dysfunction and cardiac lipotoxicity: Toll like receptor 4 as common target of the novel cardioprotective peptide cateslytin

Diagnostics of septic myocardial dysfunction in neonates

Neonatal sepsis (NS) continues to be the one of the major problems in neonatal practice. This is due to the variability of clinical manifestations and, in part, the lack of available diagnostic markers that are significantly associated with mortality as a result of neonatal sepsis. The purpose - to study the role of paraclinical markers of myocardial dysfunction in neonates with sepsis. Materials and methods. To achieve this goal, 87 newborns (the main group) with manifestations of a generalized infectious-inflammatory process were under our observation. The control group included 30 newborns, in which infectious and inflammatory diseases were refuted. Examination and treatment of patients with NS was carried out in accordance with modern international guidelines and recommendations. Results and discussion. Based on a comprehensive clinical and paraclinical examination of neonates of the main group, it was found that 25 (28.7%) newborns suffered from early sepsis, respectively, the remaining 62 (71.3%) patients had late NS. According to the severity of the condition, 76 (87.4%) children of the main group included in the study required intensive care, which was provided in the neonatal intensive care unit. The average value of procalcitonin in the main observation group was 2.53±0.33 ng/ml, respectively, in the control group - 0.24±0.04 ng/ml (p<0.05). The mean values of creatine phosphokinase, MB fraction and troponin I in the main observation group were 58.44±2.39 U/l and 0.33±0.05 ng/ml, respectively, in the control group - 41.74±2.45 U/l and 0.04±0.01 ng/ml (p<0.05). Conclusions. Generalized infectious-inflammatory process in neonates is accompanied by increased activity of cardiotropic biochemical markers. The study was conducted in accordance with the principles of the Declaration of Helsinki. The research protocol was approved by the Local Ethics Committee of the institution mentioned in the work. Informed consent of the children’s parents was obtained for the research. No conflict of interests was declared by the authors.

Hemodynamic effects and tolerance of dobutamine for myocardial dysfunction during septic shock: An observational multicenter prospective echocardiographic study.

BackgroundThe role of dobutamine during septic shock resuscitation is still controversial.MethodsThe aim of this prospective multicentre study was to comprehensively characterize the hemodynamic response of septic shock patients with systolic myocardial dysfunction to incremental doses of dobutamine (0, 5, 10, and 15 μg/kg/min).ResultsThirty two patients were included in three centers. Dobutamine significantly increased contractility indices of both ventricles [crude and afterload-adjusted left ventricular (LV) ejection fraction, global LV longitudinal peak systolic strain, tissue Doppler peak systolic wave at mitral and tricuspid lateral annulus, and tricuspid annular plane excursion) as well as global function indices (stroke volume and cardiac index) and diastolic function (increased e' and decreased E/e' ratio at lateral mitral annulus). Dobutamine also induced a significant decrease in arterial pressure and cardiac afterload indices (effective arterial elastance, systemic vascular resistance and diastolic shock index). Oxygen transport, oxygen consumption and carbon dioxide production all increased with dobutamine, without change in the respiratory quotient or lactate. Dobutamine was discontinued for poor tolerance in a majority of patients (n = 21, 66%) at any dose and half of patients (n = 15, 47%) at low-dose (5 μg/kg/min). Poor tolerance to low-dose dobutamine was more frequent in case of acidosis, was associated with lower vasopressor-free days and survival at day-14.ConclusionIn patients with septic myocardial dysfunction, dobutamine induced an overall improvement of echocardiographic parameters of diastolic and systolic function, but was poorly tolerated in nearly two thirds of patients, with worsening vasoplegia. Patients with severe acidosis seemed to have a worse response to dobutamine.

Levosimendan protects from sepsis-inducing cardiac dysfunction by suppressing inflammation, oxidative stress and regulating cardiac mitophagy via the PINK-1-Parkin pathway in mice.

BackgroundSepsis is a leading cause of death in China, the mortality rate of which is elevated when cardiac dysfunction is induced. Levosimendan is used for the treatment of decompensated cardiac failure. In this study, we sought to investigate the role of levosimendan in the inflammation, oxidative stress, and mitophagic response of the septic heart.MethodsA lipopolysaccharide (LPS)-induced septic myocardial dysfunction mouse model was established. To study the relationship between levosimendan and inflammation, oxidative stress, and mitophagy response, mice were pretreated with mdivi-1 (an inhibitor of mitophagy) prior to LPS administration. Levosimendan was given (24 µg/kg) via intraperitoneal injection 3 h after LPS had been administered. At 6 h after LPS injection, echocardiographic analysis, enzyme-linked immunosorbent assay (ELISA), oxidative stress index, myocardial pathological changes, transmission electron microscopy (TEM), immunofluorescence, and western blot were used to investigate the protective effects of levosimendan against LPS-induced myocardial dysfunction.ResultsIn the sepsis model, levosimendan markedly ameliorated myocardial dysfunction, decreased the release of myocardial enzymes and inflammatory cytokines, improved oxidative stress index and myocardial pathological changes, reduced mitochondrial division, and activated mitophagy. To confirm whether the protection of levosimendan was mediated by mitophagy, a mitophagy inhibitor-mdivi-1 was used in this study. It significantly impaired the protective effects of levosimendan. In addition, our studies further confirmed the protection of levosimendan against LPS-induced myocardial injury and the mechanisms involving PINK-1-Parkin mediated mitophagy signaling.ConclusionsLevosimendan was able to rescue the LPS-induced cardiac dysfunction mice, supporting its mechanism of action by suppressing inflammation, oxidative stress, and directly targeting the PINK-1-Parkin pathway.

MicroRNA-499 improved septic myocardial dysfunction by regulating myosin heavy chain gene axis

To investigate the role and mechanism of microRNA-499 (miR-499) regulating α-myosin heavy chain (α-MHC) and β-myosin heavy chain (β-MHC) gene axis in septic myocardial dysfunction (SMD) and its significance. Sixty healthy adult male Sprague-Dawley (SD) rats were divided into phosphate buffered saline (PBS) control group (PBS group), lipopolysaccharide (LPS) induced SMD model group (LPS group), miR-499 agonist pretreatment group (agomir+LPS group), and miR-499 inhibitor pretreatment group (antagomir+LPS group) by random number table, with 15 rats in each group. SMD rat model was reproduced by intraperitoneal injection of LPS 10 mg/kg. The PBS group was intraperitoneally injected with the same amount of PBS. The two pretreatment groups were injected with agomir 30 mg/kg or antagomir 80 mg/kg through the caudal vein for 3 days, once a day. PBS group and LPS group were not pretreated. Echocardiography was detected 5 hours after LPS injection, and relevant indexes were recorded. The expression of miR-499 in plasma and myocardial tissue was detected by real-time quantitative polymerase chain reaction (qPCR). Western blotting was used to detect the protein expressions of α-MHC and β-MHC in myocardial tissue. Plasma N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of heart failure, was measured by electrochemiluminescence. Compared with the PBS group, the rats in LPS group were depressed. Additionally, LPS down-regulated the level of miR-499 in plasma and myocardial tissue, decreased α-MHC expression in myocardial tissue and up-regulated the expression of β-MHC. Echocardiography showed that left ventricular ejection fraction (LVEF), left ventricle fractional shortening (LVFS), cardiac output (CO), stroke volume (SV) and heart rate (HR) decreased by 49.1%, 59.2%, 48.8%, 39.4% and 15.9%, respectively, and the level of plasma NT-proBNP increased significantly in LPS group, indicating that LPS could induce cardiac dysfunction in rats. Compared with the LPS group, after pretreatment with agomir to overexpress the miR-499, LVEF and LVFS were significantly increased [LVEF: 0.662±0.020 vs. 0.323±0.024, LVFS: (36.16±1.43)% vs. (20.20±1.32)%, both P < 0.01], which suggested that the cardiac function of rats was improved in agomir+LPS group. At the same time, pretreatment with agomir significantly down-regulated the β-MHC protein expression (β-MHC/GAPDH: 0.74±0.04 vs. 2.97±0.34, P < 0.01), significantly up-regulated α-MHC protein expression (α-MHC/GAPDH: 1.59±0.05 vs. 0.74±0.14, P < 0.01), and significantly decreased the plasma NT-proBNP level (ng/L: 114.49±6.85 vs. 334.13±4.36, P < 0.01). After pretreatment with antagomir to inhibit the expression of miR-499, echocardiography showed that LVEF and LVFS were significantly lower than those in the LPS group [LVEF: 0.297±0.021 vs. 0.323±0.024, LVFS: (19.38±1.52)% vs. (21.20±1.32)%, both P < 0.01], which suggested that the cardiac function of rats was significantly inhibited. At the same time, pretreatment with antagomir significantly down-regulated α-MHC protein expression in myocardial tissue (α-MHC/GAPDH: 0.63±0.03 vs. 0.74±0.14, P < 0.01), significantly up-regulated β-MHC protein expression (β-MHC/GAPDH: 3.03±0.47 vs. 2.97±0.34, P < 0.01), and significantly increased the level of plasma NT-proBNP (ng/L: 373.91±4.23 vs. 334.13±4.36, P < 0.05). miR-499 could regulate the expression of α-MHC and β-MHC which improved cardiac dysfunction caused by sepsis. Targeted regulation of miR-499 expression may be an effective way to treat SMD.

GSDMD Mediates LPS-Induced Septic Myocardial Dysfunction by Regulating ROS-dependent NLRP3 Inflammasome Activation.

Myocardial dysfunction is a serious consequence of sepsis and contributes to high mortality. Currently, the molecular mechanism of myocardial dysfunction induced by sepsis remains unclear. In the present study, we investigated the role of gasdermin D (GSDMD) in cardiac dysfunction in septic mice and the underlying mechanism. C57BL/6 wild-type (WT) mice and age-matched Gsdmd-knockout (Gsdmd -/-) mice were intraperitoneally injected with lipopolysaccharide (LPS) (10 mg/kg) to mimic sepsis. The results showed that GSDMD-NT, the functional fragment of GSDMD, was upregulated in the heart tissue of septic WT mice induced by LPS, which was accompanied by decreased cardiac function and myocardial injury, as shown by decreased ejection fraction (EF) and fractional shortening (FS) and increased cardiac troponin I (cTnI), creatine kinase isoenzymes MB (CK-MB), and lactate dehydrogenase (LDH). Gsdmd -/- mice exhibited protection against LPS-induced myocardial dysfunction and had a higher survival rate. Gsdmd deficiency attenuated LPS-induced myocardial injury and cell death. Gsdmd deficiency prevented LPS-induced the increase of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in serum, as well as IL-1β and TNF-α mRNA levels in myocardium. In addition, LPS-mediated inflammatory cell infiltration into the myocardium was ameliorated and activation of NF-κB signaling pathway and the NOD-like receptor protein 3 (NLPR3) inflammasome were suppressed in Gsdmd -/- mice. Further research showed that in the myocardium of LPS-induced septic mice, GSDMD-NT enrichment in mitochondria led to mitochondrial dysfunction and reactive oxygen species (ROS) overproduction, which further regulated the activation of the NLRP3 inflammasome. In summary, our data suggest that GSDMD plays a vital role in the pathophysiology of LPS-induced myocardial dysfunction and may be a crucial target for the prevention and treatment of sepsis-induced myocardial dysfunction.

Clinical and Laboratory Parameters Associated with Septic Myocardial Dysfunction in Children with Septic Shock.

The authors' objective was to determine the association of clinical and laboratory parameters at admission with septic myocardial dysfunction (SMD) in children with septic shock. A chart review of children aged 3 mo-17 y with fluid refractory septic shock who underwent echocardiography within 3h of admission was undertaken (2015-2017). Univariate followed by multivariate analysis was performed to identify factors associated with SMD. Of the 95 children fulfilling the inclusion criteria, SMD was diagnosed in 44 (46%) children. Children 'with SMD' had longer capillary refill time (CRT), increased lactate, lower platelet count, increased blood urea, and increased alanine aminotransferase (ALT) (p < 0.05 for all) compared to those 'without SMD'. On multivariate analysis, none of these were significant. The mortality rate was higher in those 'with SMD' than 'without SMD' [36% vs. 20% (p = 0.07)]. Prolonged CRT, increased lactate, lower platelet count, increased blood urea and elevated liver enzymes at admission may be associated with SMD in children with septic shock and may warrant early assessment of cardiac function.

Profiles of differentially expressed long noncoding RNAs and messenger RNAs in the myocardium of septic mice.

BackgroundSepsis is the primary cause of mortality in the intensive care unit (ICU), mainly due to sepsis-induced dysfunction of essential organs such as the heart and lungs. This study investigated the myocardium’s epigenetic characterization from septic mice to identify potential treatment targets for septic myocardial dysfunction.MethodsCecal ligation and puncture (CLP) was used to induce sepsis in male C57BL/6 mice. Hearts were collected 24 h after surgery to determine the expression profiles of long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) by microarray. To validate the reliability of microarray results, we randomly chose six differentially expressed lncRNAs for qRT-PCR. Functional mapping of differentially expressed mRNAs was annotated with gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses; lncRNA-mRNA co-expression network was constructed to reveal connections between lncRNAs and mRNAs.ResultsMicroarray analysis indicated that 1,568 lncRNAs and 2,166 mRNAs were differentially expressed in the myocardium from septic mice, which was further confirmed by qRT-PCR. KEGG pathway analysis showed that numerous differentially expressed mRNAs were relevant to tumor necrosis factor (TNF) and phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling pathways. Moreover, according to the lncRNA-mRNA co-expression network constructed by the above six lncRNAs and their interacting mRNAs, the co-expression network profiles had 57 network nodes and 134 connections, including 76 positive interactions and 58 negative interactions.ConclusionsIn mouse hearts, sepsis resulted in differential expression of lncRNAs and mRNAs related to TNF and PI3K-Akt signaling pathways, suggesting that lncRNAs and their interacting mRNAs may participate in the pathogenesis of septic myocardial dysfunction by regulating TNF and PI3K-Akt signaling pathways.

The Long-term Effect of Dobutamine on Intrinsic Myocardial Function and Myocardial Injury in Septic Rats with Myocardial Dysfunction.

Dobutamine (DOB) is recommended as an inotrope for septic patients with low cardiac output, but its long-term impact on sepsis-induced cardiomyopathy remains unclear. This study investigated the long-term effect of DOB on septic myocardial dysfunction and injury. Rats were exposed to cecal ligation and puncture (CLP), the intrinsic myocardial function, other organ functions, hemodynamics, inflammatory response, serum myocardial injury biomarkers, myocardial apoptosis, and vascular permeability were determined. At 6 h after CLP, the left ventricular ±dP/dt were significantly depressed, cardiac tumor necrosis factor-α and vascular cell adhesion molecule-1 expression were increased, but not serum cardiac troponin I (cTnI), N-terminal pro-brain natriuretic peptide (NT-proBNP), heart-type fatty acid-binding protein (H-FABP), creatinine, and urea nitrogen concentrations in CLP group compared with controls. At 9 h after CLP, hepatic dysfunction was present in CLP rats compared with controls. At 6 h after CLP, DOB treatment did not affect hemodynamics, the left ventricular ±dP/dt, cytokine levels in serum and myocardium, as well as cardiomyocyte apoptosis and cardiac vascular hyperpermeability at 20 h after CLP. However, DOB (10.0 μg/kg) increased serum IL-10 level and improved survival in septic rats. These results indicate that the intrinsic myocardial depression occurs earlier than hepatic and renal dysfunction in sepsis and serum cTnI, NT-proBNP, and H-FABP are not suitable as early biomarkers for sepsis-induced myocardial dysfunction. Although DOB treatment (10.0 μg/kg) in the presence of myocardial dysfunction improves survival in septic rats, it neither improves myocardial function and hemodynamics nor attenuates myocardial injury at the later stage of sepsis.

Sevoflurane Preconditioning Prevents Septic Myocardial Dysfunction in Lipopolysaccharide-Challenged Mice.

Myocardial dysfunction accompanied by severe sepsis could significantly increase the mortality rate of septic patients. This study investigated the effects and the potential mechanisms of sevoflurane preconditioning on septic myocardial dysfunction, which was induced by lipopolysaccharide (LPS; from Escherichia coli O55:B5; 18 mg/kg) in mice. Results indicated that 1 hour after the administration, LPS induced a significant increase in cell-surface Toll-like receptor 4 (TLR4), cytoplasmic IKKα protein expression, and nuclear translocation of nuclear factor kappa-B (NF-κB) protein (P < 0.05), which was attenuated by preconditioning with sevoflurane. Two hours after the administration, inhalation of sevoflurane significantly reduced the serum levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-10 (P < 0.05). Twelve hours after administration, LPS caused pathological damage to the heart and elevated the serum levels of lactate dehydrogenase (LDH) and creatine kinase-MB (P < 0.05). Echocardiography indicated that sevoflurane preconditioning significantly improved systolic and diastolic function. The inhalation of sevoflurane inhibited increases in myeloperoxidase (MPO), macrophage inflammatory protein-2 (MIP-2), TNF-α, and IL-1β levels (P < 0.05) induced by endotoxemia, whereas IL-6 release was facilitated. Sevoflurane attenuated the myocardial levels of nitric oxide (P < 0.05) without an apparent influence on malondialdehyde (MDA) or superoxide dismutase (P > 0.05). In conclusion, our study indicates that exposure to 2% sevoflurane before LPS challenge is protective against myocardial dysfunction. Sevoflurane preconditioning may attenuate neutrophil infiltration and the release of inflammatory mediators during endotoxemia.

Dexmedetomidine prevents septic myocardial dysfunction in rats via activation of α7nAChR and PI3K/Akt- mediated autophagy

Background and purposeDexmedetomidine (Dex) has been shown to elicit cardio-protective effects in sepsis. The aim of this study was to investigate the role of autophagy in the protective effects of Dex and its possible mechanism in vivo and vitro. Experimental approach6-8-week-old male Wistar rats were performed cecal ligation puncture (CLP) and administered 0.9% saline (CLP group), 50 μg/kg Dex (Dex group), Dex plus chloroquine (20 mg/kg; Dex + CQ group), or 40 μg/kg methyllycaconitin (Dex + MLA group), or 25 μM LY294002 (Dex + LY294002 group). After study, cardiac histology, cardiac function, level of autophagy, cardiomyocytes apoptosis and inflammatory mediators including protein IL-1β, IL-6, and TNF-α were measured. The LPS induced-H9C2 cardiomyocytes were treated with Dex, Dex + CQ and detected for cell apoptosis, autophagy level and cell cycle. Key resultsCLP-induced sepsis resulted in cardiac dysfunction, apoptosis, and inflammatory response. Dex exhibited protective effects on the myocardium by the induction of myocardial autophagy and ameliorated the LPS-induced blockade of autophagic flux in H9C2 cells. CQ was found to significantly inhibit Dex-mediated protection of myocardial apoptosis and inflammation. CLP rats treated with Dex in combination with MLA, an antagonist of α7 nicotinic acetylcholine receptor (α7nAChR), exhibited decreased autophagy and increased inflammation and cell death, identifying α7nAchR was involved in the Dex-mediated pathway. In addition, we found that the PI3K/Akt pathway is involved in Dex-mediated autophagy and convergent with α7nAChR-mediated stimulation of autophagy response. Conclusions and implicationsFor the first time, these data indicate that autophagy is central in Dex-mediated cardio-protection in sepsis. These observations provide the foundation for further study, and may serve as the basis for innovative therapeutic strategies against septic myocardial dysfunction.

GSK-3β inhibition protects the rat heart from the lipopolysaccharide-induced inflammation injury via suppressing FOXO3A activity.

Sepsis‐induced cardiac dysfunction represents a main cause of death in intensive care units. Previous studies have indicated that GSK‐3β is involved in the modulation of sepsis. However, the signalling details of GSK‐3β regulation in endotoxin lipopolysaccharide (LPS)‐induced septic myocardial dysfunction are still unclear. Here, based on the rat septic myocardial injury model, we found that LPS could induce GSK‐3β phosphorylation at its active site (Y216) and up‐regulate FOXO3A level in primary cardiomyocytes. The FOXO3A expression was significantly reduced by GSK‐3β inhibitors and further reversed through β‐catenin knock‐down. This pharmacological inhibition of GSK‐3β attenuated the LPS‐induced cell injury via mediating β‐catenin signalling, which could be abolished by FOXO3A activation. In vivo, GSK‐3β suppression consistently improved cardiac function and relieved heart injury induced by LPS. In addition, the increase in inflammatory cytokines in LPS‐induced model was also blocked by inhibition of GSK‐3β, which curbed both ERK and NF‐κB pathways, and suppressed cardiomyocyte apoptosis via activating the AMP‐activated protein kinase (AMPK). Our results demonstrate that GSK‐3β inhibition attenuates myocardial injury induced by endotoxin that mediates the activation of FOXO3A, which suggests a potential target for the therapy of septic cardiac dysfunction.

A multiplex analysis of sepsis mediators during human septic shock: a preliminary study on myocardial depression and organ failures

BackgroundThe mechanisms of organ failure during sepsis are not fully understood. The hypothesis of circulating factors has been suggested to explain septic myocardial dysfunction. We explored the biological coherence of a large panel of sepsis mediators and their clinical relevance in septic myocardial dysfunction and organ failures during human septic shock.MethodsPlasma concentrations of 24 mediators were assessed on the first day of septic shock using a multi-analyte cytokine kit. Septic myocardial dysfunction and organ failures were assessed using left ventricle ejection fraction (LVEF) and the Sequential Organ Failure Assessment score, respectively.ResultsSeventy-four patients with septic shock (and without immunosuppression or chronic heart failure) were prospectively included. Twenty-four patients (32%) had septic myocardial dysfunction (as defined by LVEF < 45%) and 30 (41%) died in ICU. Hierarchical clustering identified three main clusters of sepsis mediators, which were clinically meaningful. One cluster involved inflammatory cytokines of innate immunity, most of which were associated with septic myocardial dysfunction, organ failures and death; inflammatory cytokines associated with septic myocardial dysfunction had an additive effect. Another cluster involving adaptive immunity and repair (with IL-17/IFN pathway and VEGF) correlated tightly with a surrogate of early sepsis resolution (lactate clearance) and ICU survival.ConclusionsIn this preliminary study, we identified a cluster of cytokines involved in innate inflammatory response associated with septic myocardial dysfunction and organ failures, whereas the IL-17/IFN pathway was associated with a faster sepsis resolution and a better survival.

Mitochondrial derived reactive oxygen species activates NLRP3 inflammasome in cardiac fibroblasts in sepsis

BackgroundSepsis is a common disease in intensive care unit in hospital. It is caused by exaggerated host response to infection. Septic myocardial dysfunction plays an important role in pathogenesis of multiple organ failure and subsequent high mortality of patients with sepsis. Our previous studies indicate that activation of NLRP3 inflammasome in cardiac fibroblasts (CF) contributes to sepsis‐induced myocardial dysfunction. The aim of the present study is to identify the role of mitochondrial ROS (mtROS) in the activation of the NLRP3 inflammasome in CF.MethodsCultured CF was primed with LPS (1 ng/mL) followed by ATP (3 mmol/L) treatment for activation of NLRP3 inflammasome. CF mtROS was detected with MitoSOX reagent, a probe specifically detects mitochondrial ROS. NLRP3 inflammasome activation was assessed with Western blot, ELISA and co‐immunoprecipitation.ResultsATP challenge of CF primed with LPS increased CF mtROS production which was attenuated by pretreatment of the LPS primed CF with mito‐TEMPO (25 mmol/L), an ROS scavenger targeted at mtROS. ATP challenge of the LPS primed CF activated the NLRP3 inflammasome as indicated by increase in intracellular levels of NLRP3, pro‐IL‐1β and released IL‐1β. Mito‐TEMPO pretreatment of the CF with LPS+ATP prevented the increase of released IL‐1β in CF. Finally, ATP challenge of the LPS primed CF promoted NLRP3 interaction with the ASC. The Mito‐TEMPO pretreatment of the CF diminished the interaction between the NLRP3 and ASC.ConclusionOur data suggest that mitochondrial derived ROS plays a pivotal role in the activation of the CF NLRP3 inflammasome in sepsis.Support or Funding InformationThe study was supported by Natural Science Foundation of Jiangsu Province (BK20151332) and Natural Science Foundation of China (81370333).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.