Septic Cardiomyopathy Research Articles

Integrative omics analysis identifies biomarkers of septic cardiomyopathy.

Septic Cardiomyopathy (SCM) is a syndrome of acute cardiac dysfunction in septic patients, unrelated to cardiac ischemia. Multiomics studies including transcriptomics and proteomics have provided new insights into the mechanisms of SCM. In here, a rat model of SCM was established by intraperitoneal injection of lipopolysaccharide (LPS). Biomarkers of SCM were characterized via a multi-omics analysis. The differentially expressed (DE) mRNAs predominantly appeared in pathways linked to the immune response, inflammatory response, and the complement and coagulation cascades, while DE proteins were mainly enriched in pathways associated with the complement and coagulation cascades. On this basis, the integrated analysis was performed between transcriptome and proteome. The potential biomarkers were further verified by RT-qPCR and WB. The current proteotranscriptomic research has furnished a valuable dataset and fresh perspectives that will enhance our comprehension of the development of SCM. This, in turn, is expected to expedite the formulation of novel approaches for the prevention and management of SCM in patients.

Astragaloside IV alleviates septic myocardial injury through DUSP1-Prohibitin 2 mediated mitochondrial quality control and ER-autophagy.

Septic cardiomyopathy (SCM) is a complication of myocardial injury in patients with severe sepsis. This study highlights the potential of Astragaloside IV(AS) in the treatment of septic cardiomyopathy and provides a reference for developing cardioprotective drugs targeting DUSP1-PHB2-related mitochondria-ER interaction. Dual specificity phosphatase-1 (DUSP1)/Prohibitin 2 cardiomyocyte-specific knockout mice (DUSP1/PHB2CKO) /DUSP1 transgenic mice (DUSP1/PHB2TG) were used to generate LPS-induced sepsis models. The pathological mechanism by which AS-IV improves heart injury was detected using cardiac ultrasound, fluorescence staining, transmission electron microscopy, and western blotting. After siRNA treatment of cardiomyocytes with DUSP-1/PHB2, changes in mitochondrial function and morphology were determined using qPCR, western blotting, ELISA, and laser confocal microscopy, and the targeted therapeutic effects of AS-IV were further examined. SCM treatment leads to severe mitochondrial dysfunction. However, Astragaloside IV (AS) treatment normalizes mitochondrial homeostasis and ER function. Notably, the protective effect was blocked in DUSP1/Prohibitin 2 cardiomyocyte-specific knockout mice (DUSP1/PHB2CKO) but remained unaffected in DUSP1 transgenic mice (DUSP1/PHB2TG). This study highlights the potential of AS in the treatment of septic cardiomyopathy and provides a reference for developing cardioprotective drugs targeting DUSP1-PHB2 related mitochondria-ER interaction.

Deletion of MAPL ameliorates septic cardiomyopathy by mitigating mitochondrial dysfunction.

Mitochondrial dysfunction is a critical factor in the pathogenesis of septic cardiomyopathy (SCM). Mitochondrial anchored protein ligase (MAPL), a small ubiquitin-like modifier (SUMO) E3 ligase, plays a significant role in mitochondrial function. However, the role of MAPL in SCM remains unclear. To investigate the role of MAPL in SCM, cardiomyocyte-specific MAPL knockout mice were generated. A cecal ligation and puncture (CLP) procedure was employed to induce a sepsis-like condition. The expression of MAPL in heart tissues and H9C2 cardiomyocytes was elevated following CLP challenge or lipopolysaccharide (LPS) stimulation. MAPL deficiency ameliorated CLP-induced cardiac injury, dysfunction, and inflammation, and also improved the survival rate of mice following CLP operation. Additionally, MAPL deficiency or knockdown inhibited LPS-induced cardiomyocyte apoptosis, improved mitochondrial structural abnormalities, and increased ATP production. Furthermore, MAPL knockdown mitigated LPS-induced reductions in mitochondrial membrane potential (MMP) and intracellular reactive oxygen species (ROS) production. Mechanistically, the expression of dynamin-related protein 1 (drp1) in the mitochondria of heart tissues or H9C2 cardiomyocytes was elevated under septic conditions. Accordingly, the SUMOylation of drp1 in heart tissues or H9C2 cardiomyocytes was increased under sepsis conditions, which was reduced by MAPL knockout or knockdown. Our results reveal that MAPL promotes cardiac injury/dysfunction and inflammation in SCM. Deficiency or knockdown of MAPL alleviates SCM by reducing drp1 SUMOylation as well as drp1-mediated mitochondrial dysfunction. These findings suggest that targeting MAPL may represent a therapeutic strategy for patients with SCM.

Berberine ameliorates septic cardiomyopathy through protecting mitochondria and upregulating Notch1 signaling in cardiomyocytes

IntroductionSeptic cardiomyopathy (SCM) arises as a consequence of sepsis-associated cardiovascular dysfunction, for which there is currently no specific targeted therapy available. Previous studies have demonstrated the beneficial therapeutic effect of berberine (BBR) on SCM; however, the underlying mechanisms of action remain unclear. The objective of this is to elucidate how BBR alleviates SCM.MethodsSeptic cardiomyopathy rat model was established by performing cecal ligation and puncture (CLP), while a cardiomyocyte injury model was provoked in H9C2 cells using lipopolysaccharide (LPS). Cardiac function was assessed through echocardiography, and myocardial histopathology was examined with hematoxylin-eosin (HE) staining. Cardiomyocyte viability was determined through Cell Counting Kit-8 (CCK8) assay, and measurement of ATP levels was done with an ATP assay kit. Mitochondrial ultrastructure was observed using transmission electron microscopy. Real-time polymerase chain reaction (RT-PCR) and Western blotting were employed to analyze the expression of Notch1 signaling pathway components and downstream molecules in myocardial tissues and cells.ResultIn vivo, BBR markedly improved symptoms and cardiac function in SCM rats, leading to enhanced ATP content, and ameliorated mitochondrial structure. Additionally, BBR increased Notch1 protein expression in myocardial tissue of the rats. In vitro, BBR elevated the survival rates of H9C2 cell, improved mitochondrial morphology, and raised ATP levels. The mRNA expression of Notch1, Hes1, and Hes2, and Notch1 protein expression was upregulated by BBR. While these effects were reversed upon inhibiting the Notch1 signaling pathway.ConclusionBBR improves septic cardiomyopathy by modulating Notch1 signaling to protect myocardial mitochondria.

Transcriptomics changes of calcitonin gene-related peptide in mitigating lipopolysaccharide-induced septic cardiomyopathy

Septic cardiomyopathy (SCM), a complication initiated by sepsis, presents a significant clinical challenge, leading to increased mortality rates. However, the mechanisms of SCM have not been fully uncovered. Our study involved analyzing RNA sequencing (RNA-seq) data from rat heart tissue, along with utilizing molecular docking and molecular dynamics (MD) simulations, to discover key targets and potential pharmacological actions of the calcitonin gene-related peptide (CGRP) against SCM. A lipopolysaccharide-induced SCM model was established in rats (LPS 10 mg/kg, intraperitoneal (i.p.)). Thereafter, the myocardial tissues from the three groups of rats (Ctrl group, LPS group, and CGRP group) (n = 5) were extracted and underwent RNA-seq, followed by bioinformatics analyses. The qPCR-validated hub targets potentially interacting with CGRP were identified. Following this, homology modeling was utilized to obtain the 3D structure of hub targets, and molecular docking was conducted to evaluate the interaction between CGRP and hub targets. MD simulations (300 ns) were performed to confirm the findings further. Our findings demonstrated that CGRP significantly lowered mortality in SCM rats. 633 DEGs were affected by LPS, contrasted with the Ctrl group. 96 DEGs were affected by CGRP compared to the LPS group. In total, ten fully annotated CGRP-triggered hub genes were obtained. The molecular docking and MD simulations indicate that the relationship between CGRP and eight hub genes is extremely strong. This research offers a thorough examination of the possible objectives and fundamental molecular processes of CGRP in combating SCM, laying the groundwork for investigating the potential protective mechanisms of CGRP against SCM.

TSPO Exacerbates Sepsis-Induced Cardiac Dysfunction by Inhibiting p62-Mediated Autophagic Flux via the ROS-RIP1/RIP3-Exosome Axis

Septic cardiomyopathy (SCM) is a critical complication of sepsis, primarily attributed to mitochondrial dysfunction and impaired autophagic flux. This study explores the role of translocator protein (TSPO) in SCM pathogenesis and assesses its potential as a therapeutic target. We identified increased TSPO expression in plasma samples from sepsis patients, with further validation in septic rats and LPS-stimulated H9C2 cardiomyocytes. Elevated TSPO disrupted mitochondrial function, leading to increased reactive oxygen species (ROS) production and activation of the RIP1/RIP3 pathway, which hindered p62-positive autophagosome degradation and promoted inflammation. Moreover, exosome release containing TSPO-positive autophagosomes into plasma may exacerbate systemic inflammation. NADH, identified as a TSPO-binding molecule, restored autophagic flux, improved mitochondrial function, and enhanced cardiac performance and survival in septic rats. These findings suggest that targeting TSPO with NADH could alleviate mitochondrial dysfunction and inflammatory responses in SCM, providing a promising therapeutic strategy for sepsis-induced cardiac injury.

From Kidney Crisis to Heart Revival: A Case of Septic Cardiomyopathy Following Septic Shock Induced by Xanthogranulomatous Pyelonephritis

From Kidney Crisis to Heart Revival: A Case of Septic Cardiomyopathy Following Septic Shock Induced by Xanthogranulomatous Pyelonephritis

Mitochondrial abnormalities in septic cardiomyopathy.

Septic cardiomyopathy is a common complication in patients with sepsis, and is one of the indicators of poor prognosis. Its pathogenesis is complex, involving calcium ion imbalance in cardiomyocytes, nitric oxide (NO) synthesis disorder, mitochondrial abnormalities and immune inflammatory reaction, especially mitochondrial abnormalities. In this paper, the mechanism of mitochondrial abnormalities causing septic cardiomyopathy was discussed from the aspects of mitochondrial structure change, mitochondrial energy metabolism disorder, redox imbalance, mitochondrial calcium overload, mitochondrial biosynthesis and autophagy abnormalities.

MMP-8 causes leftward shift in end-diastolic pressure-volume relationship and may explain the development of diastolic dysfunction in septic cardiomyopathy.

Septic cardiomyopathy (SCM) with diastolic dysfunction carries a poor prognosis, and the mechanisms underlying the development of diastolic dysfunction remain unclear. Matrix metalloproteinase-8 (MMP-8) is released from neutrophils and degrades collagen I. MMP-8 levels correlate with SCM severity. We scrutinized, for the first time, the direct impact of MMP-8 on cardiac systolic and diastolic functions. Isolated rat hearts were perfused with Krebs-Henseleit solution in a Langendorff setup with computer-controlled filling pressures of both ventricles in an isovolumetric regime. The end-diastolic pressure (EDP) varied periodically between 3 and 20 mmHg. After baseline recordings, MMP-8 (100 µg/mL) was added to the perfusion. Short-axis views of both ventricles were continuously acquired by echocardiography. MMP-8 perfusion resulted in a progressive decline in peak systolic pressures (Psys) in both ventricles, but without significant changes in their end-systolic pressure-area relationships (ESPARs). Counterintuitively, conspicuous leftward shifts of the end-diastolic pressure-area relationships (EDPARs) were observed in both ventricles. The left ventricle (LV) end-diastolic area (EDA) decreased by 32.8 ± 5.7% (P = 0.008) at an EDP of 10.5 ± 0.4 mmHg, when LV Psys dropped by 20%. The decline of Psys was primarily due to the decrease in EDA, and restoring the baseline EDA by increasing EDP recovered 81.33 ± 5.87% of the pressure drop. Collagen I generates tensile (eccentric) stress, and its degradation by MMP-8 causes end-diastolic pressure-volume relationship (EDPVR) leftward shift, resulting in diastolic and systolic dysfunctions. The diastolic dysfunction explains the clinically observed fluid unresponsiveness, whereas the decrease in end-diastolic volume (EDV) diminishes the systolic functions. MMP-8 can explain the development of SCM with diastolic dysfunction.NEW & NOTEWORTHY MMP-8, released from activated neutrophils and macrophages, is markedly elevated in sepsis, correlating with sepsis severity and mortality. MMP-8 targets collagen I of the cardiac ECM and induces diastolic dysfunction with fluid unresponsiveness, associated with decreased EDV, reduced sarcomere length, and diminished systolic function. Unlike other MMPs that predominantly cleave collagen-III and contribute to cardiac dilatation, thereby increasing sarcomere length, MMP-8 leads to a leftward shift in the EDPVR, resulting in diastolic and systolic dysfunctions.

Construction and Evaluation of a Risk Prediction Model for Septic Cardiomyopathy Based on MIMIC-Ⅳ Database

Objective To analyze the risk factors of septic cardiomyopathy (SC),and to construct and evaluate the risk prediction model of SC. Methods The clinical data of patients with sepsis were extracted from MIMIC-Ⅳ database and randomized into a training set and a validation set at a ratio of 7 to 3.According to the presence or absence of SC,the patients were assigned into SC and non-SC groups.The independent risk factors of SC were determined by univariate and multivariate Logistic regression analysis,and a risk prediction model and a nomogram were established.The area under the receiver operating characteristic curve (AUC),calibration curve,and decision curve analysis (DCA) were employed to evaluate the distinguishing degree,calibration,and clinical applicability of the model,respectively. Results A total of 2628 sepsis patients were enrolled in this study,including 1865 patients in the training set and 763 patients in the validation set.There was no significant difference in the incidence of SC between the training set and the validation set (58.98% vs. 62.25%,P=0.120).Except chronic obstructive pulmonary disease (P=0.015) and length of stay in intensive care unit (P=0.016),there was no significant difference in other clinical indicators between the two groups (all P>0.05).Logistic regression analysis showed that coronary heart disease (P=0.028),heart failure (P<0.001),increased neutrophil count (P=0.001),decreased lymphocyte count (P=0.036),increased creatine kinase isoenzyme (P<0.001),and increased blood urea nitrogen (P=0.042) were independent risk factors for SC.The AUC of the nomogram prediction model in the training set and validation set was 0.759 (95% CI=0.732-0.785) and 0.765 (95% CI=0.723-0.807),respectively.The established model showcased good fitting degrees in both data sets (training set:P=0.075;validation set:P=0.067).The DCA results showed that the nomogram prediction model had good clinical applicability. Conclusion The nomogram prediction model based on basic diseases and clinical biochemical indicators can effectively predict the risk of SC occurrence.

The role of TREM-1 in septic myocardial pyroptosis and septic cardiomyopathy in vitro and in vivo.

Septic cardiomyopathy (SCM) is an acute cardiac dysfunction involving myocardial cell pyroptosis. TREM-1 is a known receptor on cell membrane that can amplify the inflammatory response. Our previous studies have shown that TREM-1 in cardiomyocytes is involved in the activation of NLRP3 through the SMC4/NEMO pathway. Here, we aimed to use Trem-1 and Nlrp3 knockout mice to verify the effect of TREM-1 through NLRP3 on cardiac function in septic mice. The results showed that TREM-1 knockout resulted in a decrease in the release of downstream cell signals, including SMC4 and NLRP3, resulting in a decrease in cytokine release and improvement of cardiac dysfunction. Knockout of NLRP3 also reduced cardiomyocyte pyroptosis and increased survival rate. The therapeutic targeting of TREM-1 activation of NLRP3 and its pathway may contribute to the treatment or prevention of SCM.

Ablation of mitophagy receptor FUNDC1 accentuates septic cardiomyopathy through ACSL4-dependent regulation of ferroptosis and mitochondrial integrity

Sepsis evokes compromised myocardial function prompting heart failure albeit target therapy remains dismal. Our study examined the possible role of mitophagy receptor FUNDC1 in septic cardiomyopathy. A sepsis model was established using cecal ligation and puncture (CLP) in FUNDC1 knockout (FUNDC1−/−) and WT mice prior to the evaluation of cardiac morphology, echocardiographic and cardiomyocyte contractile, oxidative stress, apoptosis, necroptosis, and ferroptosis. RNAseq analysis depicted discrepant patterns in mitophagy, oxidative stress and ferroptosis between CLP-challenged and control murine hearts. Septic patients displayed cardiac injury alongside low plasma FUNDC1 and iron levels. CLP evoked interstitial fibrosis, cardiac dysfunction (lowered ejection fraction, fractional shortening, shortening/relengthening velocity, peak shortening and electrically-stimulated intracellular Ca2+ rise, alongside increased LV end systolic diameter and relengthening duration), O2− buildup, apoptosis, necroptosis, and ferroptosis (downregulated GPX4 and SLC7A11), the responses of which were accentuated by FUNDC1 ablation. In particular, levels of lipid peroxidation enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4) were upregulated following CLP procedure, with a more pronounced response in FUNDC1−/− mice. Co-immunoprecipitation and interaction interface revealed an evident interaction between FUNDC1 and ACSL4. In vitro studies revealed that the endotoxin lipopolysaccharide provoked cardiomyocyte contractile and lipid peroxidation anomalies, the responses were reversed by the mitophagy inducer oleanolic acid, inhibition of ACSL4 and ferroptosis. These findings favor a role for FUNDC1-ACSL4-ferroptosis cascade in septic cardiomyopathy.

Toll-like Receptors: Therapeutic Potential in Life Threatening Diseases-Cardiac Disorders.

Toll-like receptors (TLRs) belong to the innate immune system. TLRs identify and respond to invading pathogens by recognizing certain molecular patterns associated with the infections. TLRs are crucial for the host's defence against these diseases. TLRs are capable of detecting several endogenous chemicals through the recognition of damage-associated molecular patterns, which are generated in response to various harmful situations. Recent animal studies have shown that TLR signaling has a significant role in the development of serious heart diseases, such as ischemia myocardial damage, myocarditis, and septic cardiomyopathy, where inflammation of the heart muscle is a key factor. This manuscript examines the animal research findings on (1) TLRs, TLR ligands, and the signal transduction system, and (2) the significant involvement of TLR signaling in these crucial cardiac diseases.

Investigating immune dysregulation and hub genes in septic cardiomyopathy development

Septic cardiomyopathy is a life-threatening heart dysfunction caused by severe infection. Considering the complexity of pathogenesis and high mortality, the identification of efficient biomarkers are needed to guide clinical practice. Based on multimicroarray analysis, this study aimed to explore the pathogenesis of septic cardiomyopathy and the related immune landscape. The results showed that septic cardiomyopathy resulted in organ dysfunction due to extreme pro- and anti-inflammatory effects. In this process, KLRG1, PRF1, BCL6, GAB2, MMP9, IL1R1, JAK3, IL6ST, and SERPINE1 were identified as the hub genes regulating the immune landscape of septic cardiomyopathy. Nine transcription factors regulated the expression of these genes: SRF, STAT1, SP1, RELA, PPARG, NFKB1, PPARA, SMAD3, and STAT3. The hub genes activated the Th17 cell differentiation pathway, JAK-STAT signaling pathway, and cytokine‒cytokine receptor interaction pathway. These pathways were mainly involved in regulating the inflammatory response, adaptive immune response, leukocyte-mediated immunity, cytokine-mediated immunity, immune effector processes, myeloid cell differentiation, and T-helper cell differentiation. These nine hub genes could be considered biomarkers for the early prediction of septic cardiomyopathy.

ZC3H13 may participate in the ferroptosis process of sepsis-induced cardiomyopathy by regulating the expression of Pnn and Rbm25

BackgroundN6 methyladenosine (m6A) regulates the ferroptosis in different diseases. However, there is no report about the role of the m6A regulator in the ferroptosis process of septic cardiomyopathy (SCM). This study aims to find the potential m6A regulator that participates in the ferroptosis process of SCM. MethodsGenes related to m6A were identified through bioinformatics analysis in GSE142615. Then, the expression of Rrp8, Trmt6, Trmt61a, Ythdf1, and ZC3H13 was detected in lipopolysaccharide (LPS)-treated HL-1 cells using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). After overexpression or interference with ZC3H13, Cell Counting Kit-8 measured cell proliferation, flow cytometry detected apoptosis and reactive oxygen species (ROS) accumulation was observed. Then, we identified the potential downstream genes of ZC3H13 through further bioinformatics analysis followed by qRT-PCR and western blotting validation. ResultsThere were five differentially expressed genes related to m6A, including Rrp8, Trmt6, Trmt61a, Ythdf1, and ZC3H13. The expression of Rrp8, Trmt6, Trmt61a, Ythdf1, and ZC3H13 mRNA was significantly up-regulated in the LPS-treated HL-1 cells, with ZC3H13 having the highest expression. Furthermore, overexpression of ZC3H13 inhibited the proliferation of HL-1 cells and promoted apoptosis and ROS accumulation. While, interfering with ZC3H13 promoted the proliferation of LPS-treated HL-1 cells, and reduced apoptosis and ROS accumulation. Additionally, si-ZC3H13 promoted the expression of Pnn, GPX4, and SLC7A11; while inhibiting the expression of Rbm25 and Caspase 3. ConclusionsIn a word, the silence of ZC3H13 increased the proliferation and ferroptosis-related protein expression, decreased apoptosis and ROS accumulation, as well as maybe by regulating Pnn and Rbm25 expression.

ALCAT1-Mediated Pathological Cardiolipin Remodeling and PLSCR3-Mediated Cardiolipin Transferring Contribute to LPS-Induced Myocardial Injury.

Cardiolipin (CL), a critical phospholipid situated within the mitochondrial membrane, plays a significant role in modulating intramitochondrial processes, especially in the context of certain cardiac pathologies; however, the exact effects of alterations in cardiolipin on septic cardiomyopathy (SCM) are still debated and the underlying mechanisms remain incompletely understood. This study highlights a notable increase in the expressions of ALCAT1 and PLSCR3 during the advanced stage of lipopolysaccharide (LPS)-induced SCM. This up-regulation potential contribution to mitochondrial dysfunction and cellular apoptosis-as indicated by the augmented oxidative stress and cytochrome c (Cytc) release-coupled with reduced mitophagy, decreased levels of the antiapoptotic protein B-cell lymphoma-2 (Bcl-2) and lowered cell viability. Additionally, the timing of LPS-induced apoptosis coincides with the decline in both autophagy and mitophagy at the late stages, implying that these processes may serve as protective factors against LPS-induced SCM in HL-1 cells. Together, these findings reveal the mechanism of LPS-induced CL changes in the center of SCM, with a particular emphasis on the importance of pathological remodeling and translocation of CL to mitochondrial function and apoptosis. Additionally, it highlights the protective effect of mitophagy in the early stage of SCM. This study complements previous research on the mechanism of CL changes in mediating SCM. These findings enhance our understanding of the role of CL in cardiac pathology and provide a new direction for future research.

Bioinformatics analysis of neutrophil-associated hub genes and ceRNA network construction in septic cardiomyopathy.

Septic cardiomyopathy (SCM) is a critical sepsis complication characterized by reversible cardiac depression during early septic shock. Neutrophils, integral to innate immunity, can mediate organ damage when abnormal, but their specific role in sepsis-induced myocardial damage remains elusive. Our study focuses on elucidating the role of Neutrophil-Related Genes (NRGs) in SCM, finding early diagnosis and treatment biomarkers. We identified shared differentially expressed genes (DEGs) from datasets GSE79962 and GSE44363 and pinpointed hub DEGs using the cytoHubba plugin in Cytoscape software. The Neutrophil-Related Hub Gene (NRHG) MRC1 was identified via intersecting hub DEGs with NRGs from WGCNA. We validated MRC1's abnormal expression in SCM using our data and external datasets. Furthermore, a neutrophil-related ceRNA network (AC145207.5/ miR-23a-3p/MRC1) was constructed and validated. Our findings reveal MRC1 as a potential NRHG in SCM pathogenesis, offering insights into neutrophil-mediated mechanisms in SCM and providing a novel molecular target for early diagnosis and intervention in SCM.

Endothelial α1-adrenergic receptor activation improves cardiac function in septic mice via PKC-ERK/p38MAPK signaling pathway

Cardiomyopathy is particularly common in septic patients. Our previous studies have shown that activation of the alpha 1 adrenergic receptor (α1-AR) on cardiomyocytes inhibits sepsis-induced myocardial dysfunction. However, the role of cardiac endothelial α1-AR in septic cardiomyopathy has not been determined. Here, we identified α1-AR expression in mouse and human endothelial cells and showed that activation of α1-AR with phenylephrine (PE) improved cardiac function and survival by preventing cardiac endothelial injury in septic mice. Mechanistically, activating α1-AR with PE decreased the expression of ICAM-1, VCAM-1, iNOS, E-selectin, and p-p38MAPK, while promoting PKC and ERK1/2 phosphorylation in LPS-treated endothelial cells. These effects were abolished by a PKC inhibitor or α1-AR antagonist. PE also reduced p65 nuclear translocation, but this suppression is not blocked by PKC inhibition. Treatment with U0126 (a specific ERK1/2 inhibitor) reversed the effects of PE on p38MAPK phosphorylation. Our results demonstrate that cardiac endothelial α1-AR activation prevents sepsis-induced myocardial dysfunction in mice by inhibiting the endothelial injury via PKC-ERK/p38MAPK signaling pathway and a PKC-independent inhibition of p65 nuclear translocation. These findings offer a new perspective for septic patients with cardiac dysfunction by inhibiting cardiac endothelial cell injury through α1-AR activation.

Panaxadiol Saponin alleviates LPS-induced cardiomyopathy similar to dexamethasone via improving mitochondrial quality control.

Septic cardiomyopathy is linked to a dysregulation in mitochondrial integrity and elevated mortality rates, for which an efficacious treatment remains elusive. PDS, a panaxadiol saponin extracted from ginseng stem and leaf. This study identified the protective effects of PDS and DEX in LPS-induced cardiomyopathy and explored the mechanism of them treating LPS-induced cardiomyopathy from the perspectives of mitochondrial quality control. DEX and PDS enhance antioxidant defense by degrading Keap1 to activate Nrf2, activate mitochondrial occurrence protein PGC-1α and fusion protein OPA1, Mfn1, Mfn2 expression, inhibit phosphorylation of mitochondrial fission protein Drp1, aiming to maintain normal structure and function of mitochondrial, thereby preserving oxidative phosphorylation capacity. In summary, our findings highlighted that the protective efficacy of PDS and DEX in maintaining mitochondrial in LPS-induced cardiomyopathy, and mechanism improving mitochondrial quality control at least in part by promoting Nrf2 activation.

Progress of heparanase in septic cardiomyopathy: A review.

Septic cardiomyopathy (SCM) is a severe complication caused by sepsis, resulting in a high mortality rate. The current understanding of the pathogenic mechanism of SCM primarily involves endocardial injury, microcirculation disturbance, mitochondrial dysfunction and fibrosis. Heparanase (HPA), an endo-β-D-glucuronidase, has been implicated in inflammation, immune response, coagulation promotion, microcirculation disturbance, mitochondrial dysfunction and fibrosis. Therefore, it was hypothesized that HPA may play an important role in the pathogenesis of SCM. The present study provides a summary of various pathophysiological changes and mechanisms behind the involvement of HPA in SCM. It also presents a novel perspective on the pathogenic mechanism, diagnosis and treatment of SCM.