Sepsis-induced Myocardial Dysfunction Research Articles

Carvacrol alleviates LPS-induced myocardial dysfunction by inhibiting the TLR4/MyD88/NF-κB and NLRP3 inflammasome in cardiomyocytes.

Sepsis-induced myocardial dysfunction (SIMD) may contribute to the poor prognosis of septic patients. Carvacrol (2-methyl-5-isopropyl phenol), a phenolic monoterpene compound extracted from various aromatic plants and fragrance essential oils, has multiple beneficial effects such as antibacterial, anti-inflammatory, and antioxidant properties. These attributes make it potentially useful for treating many diseases. This study aims to investigate the effects of CAR on LPS-induced myocardial dysfunction and explore the underlying mechanism. H9c2 cells were stimulated with 10µg/ml LPS for 12h, and c57BL/6 mice were intraperitoneally injected with 10mg/kg LPS to establish a septic-myocardial injury model. Our results showed that CAR could improve cardiac function, significantly reduce serum levels of inflammatory cytokines (including TNF-α, IL-1β, and IL-6), decrease oxidative stress, and inhibit cardiomyocyte apoptosis in LPS-injured mice. Additionally, CAR significantly downregulated the expression of TLR4, MyD88, and NF-κB in LPS-injured mice and H9c2 cells. It also inhibited the upregulation of inflammasome components (such as NLRP3, GSDMD, and IL-1β) in H9c2 cells triggered by LPS. Taken together, CAR exhibited potential cardioprotective effects against sepsis, which may be mainly attributed to the TLR4/MyD88/NF-κB pathway and the NLRP3 inflammasome.

Endothelial-derived exosomes: A novel therapeutic strategy for LPS-induced myocardial damage with anisodamine

Sepsis-induced myocardial dysfunction presents significant challenges in clinical management and is associated with increased mortality. Anisodamine (654–1/−2) has potentials in alleviating cardiac and endothelial impairments associated with sepsis. Exosomes, small vesicles secreted by cells, carry various bioactive molecules, such as nucleic acids, proteins, and lipids. These vesicles can travel to target cells to influence their function and modulating biological processes. In the context of endothelial-cardiac crosstalk, exosomes derived from endothelial cells can transfer signals that either exacerbate or mitigate myocardial injury, playing a crucial role in the progression of cardiovascular diseases. However, the precise role of endothelial-cardiac crosstalk, particularly through exosomes, in mediating the cardioprotective effects of anisodamine remains unclear. This study evaluated the effects of anisodamine on myocardial and endothelial injuries induced by LPS. Mechanisms were analyzed through network pharmacology, molecular docking, Western blotting, and RT-qPCR. The interaction between endothelial and cardiomyocyte inflammatory responses to anisodamine was assessed using a co-culture assay. Furthermore, both in vivo and in vitro assays were conducted to evaluate the effects of anisodamine-/LPS- treated HUVECs exosomes on A16 cell and myocardial function in mice. Anisodamine effectively mitigated apoptosis, inflammation, mitochondrial and myocardial injury, glycocalyx degradation, and oxidative stress by regulating the PI3K-AKT, NLRP-3/Caspase-1/ASC, TNF-α/PKCα/eNOs/NO, and NF-κB/iNOs/NO pathways in A16 cells and HUVECs. Moreover, in vivo and in vitro assays confirmed the protective effects of anisodamine against myocardial injuries mediated by exosomes derived from LPS-treated HUVECs. In summary, anisodamine ameliorated inflammation-induced endothelial and cardiomyocyte dysfunction. The in vitro and in vivo assays demonstrated that anisodamine could alleviate myocardial dysfunction through exosome-mediated mechanisms, offering new therapeutic avenues for treating myocardial injury and highlighting the potential of targeted exosome therapy in clinical settings.

GPR30 Agonist G1 Mitigates Sepsis-Induced Cardiac Dysfunction by Inhibiting ACE2/c-FOS-Mediated Necroptosis in Female Mice.

Sepsis is a severe inflammatory syndrome with high mortality and morbidity. Sepsis-induced myocardial dysfunction (SIMD) is a common cause of death in sepsis. The female sex is less susceptible to sepsis-related organ dysfunction, although the underlying mechanism of this sex difference remains unclear. This study explored the role of estrogen receptor G protein-coupled estrogen receptor 30 (GPR30) in septic cardiac dysfunction. Results from the present study indicated that GPR30 activation by the G1 agonist protected female mouse hearts against SIMD exposed to lipopolysaccharides. However, this beneficial effect was absent in female ACE2-knockout mice, as demonstrated by poorer cardiac contractility, myocardial injury, and necroptosis. We also demonstrated that the Stat6 transcription factor induced ace2 transcription by enhancing its promoter activity under GPR30 activation in septic hearts. The adenovirus-mediated inhibition of ACE2 targeting c-FOS expression reversed the deterioration, restored cardiac function, and improved survival in female ACE2-knockout mice. These results demonstrate the essential role of GPR30/STAT6/ACE2/c-FOS-mediated necroptosis in G1-mediated protection and provide novel insight into the pathogenesis of sepsis-related organ damage.

Propofol Ameliorates Sepsis-Induced Myocardial Dysfunction via Anti-Apoptotic, Anti-Oxidative Properties, and mTOR Signaling.

Sepsis often leads to cardiomyopathy, contributing to increased mortality rates. 2,6-Diisopropylphenol (propofol), an anesthetic, has demonstrated efficacy in protecting cardiomyocytes from cell death caused by hypoxia and reoxygenation. This study examined the effects of propofol on sepsis-associated myocardial dysfunction and explored the underlying mechanism of action. Mice and rat cardiomyocytes (H9C2 cell line) were used to establish a sepsis-induced myocardial dysfunction model. Lipopolysaccharides (LPS)-treated mice and H9C2 cells were treated with propofol, with rapamycin used for mechanistic studies in H9C2 cells. Cardiac function was evaluated by echocardiographic measurements. Heart tissues were stained with hematoxylin and eosin, and heart weight/body weight ratio along with the levels of cardiac biomarkers were measured using Enzyme Linked Immunosorbent Assay (ELISA). Activation of the mammalian target of rapamycin (mTOR) pathway was assessed by western blotting. Apoptosis in heart tissues and H9C2 cells was evaluated using Terminal deoxynucleotidyl transferase (TdT) dUTP nick end labeling (TUNEL) assay, and cell viability was quantified using Cell Counting Kit (CCK)-8 assay. Oxidative stress in H9C2 cells was assessed by measuring reactive oxygen species (ROS) levels through immunofluorescence staining and malondialdehyde (MDA) and superoxide dismutase (SOD) levels using ELISA. Propofol reversed LPS-induced myocardial changes and cardiac dysfunction (p < 0.05). In mouse tissues and H9C2 cells, propofol reversed LPS-induced mTOR pathway inhibition and apoptosis (p < 0.001). Moreover, propofol alleviated oxidative stress in LPS-treated cells. The activation of the mTOR pathway by propofol, along with its inhibitory effects on oxidative stress and apoptosis in cardiomyocytes, was negated by rapamycin (p < 0.001). Propofol ameliorates sepsis-induced myocardial dysfunction triggered by LPS through the mTOR pathway, thereby promoting antioxidative stress and reducing cell apoptosis.

Immune-response gene 1 deficiency aggravates inflammation-triggered cardiac dysfunction by inducing M1 macrophage polarization and aggravating Ly6Chigh monocyte recruitment

The immune response gene 1 (IRG1) and its metabolite itaconate are implicated in modulating inflammation and oxidative stress, with potential relevance to sepsis-induced myocardial dysfunction (SIMD). This study investigates their roles in SIMD using both in vivo and in vitro models. Mice were subjected to lipopolysaccharide (LPS)-induced sepsis, and cardiac function was assessed in IRG1 knockout (IRG1-/-) and wild-type mice. Exogenous 4-octyl itaconate (4-OI) supplementation was also examined for its protective effects. In vitro, bone marrow-derived macrophages and RAW264.7 cells were treated with 4-OI following Nuclear factor, erythroid 2 like 2 (NRF2)–small interfering RNA administration to elucidate the underlying mechanisms. Our results indicate that IRG1 deficiency exacerbates myocardial injury during sepsis, while 4-OI administration preserves cardiac function and reduces inflammation. Mechanistic insights reveal that 4-OI activates the NRF2/HO-1 pathway, promoting macrophage polarization and attenuating inflammation. These findings underscore the protective role of the IRG1/itaconate axis in SIMD and suggest a therapeutic potential for 4-OI in modulating macrophage responses.

Sodium octanoate mediates GPR84-dependent and independent protection against sepsis-induced myocardial dysfunction

IntroductionThis study aims to evaluate the therapeutic effects of sodium octanoate (SO), a medium-chain fatty acid salt, on SIMD in a murine model and to explore its underlying mechanisms. MethodsMale mice were subjected to sepsis models through two methods: intraperitoneal injection of lipopolysaccharide (LPS) and cecal ligation and punction (CLP). Mice received interval doses of SO every 2 hours or 4 hours for a total of six times or three times after LPS treatment. The relationship between SO and G protein-coupled receptor 84 (GPR84) was evaluated through GEO data analysis and molecular docking studies. DBA/2 mice were used to study the role of the GPR84 protein in the SO-mediated protection. Energy metabolomics was utilized to comprehensively assess the impact of SO on the levels of cardiac energy metabolic products in septic mice. histone modification identification techniques were used to further identify the specific sites of histone modification in the hearts of SO-treated septic mice. ResultsSO treatment significantly improved myocardial contractile function, restored the oxidative stress imbalance and enhanced the myocardium's resistance to oxidative injury. SO significantly promotes the expression of GPR84. The loss of GPR84 function markedly attenuates the protective effects of SO. SO enhanced myocardial energy metabolism by promoting the synthesis of acetyl-CoA and upregulating genes involved in fatty acid β-oxidation which were abolished by medium-chain acyl-CoA dehydrogenase (MCAD) knockdown. SO induced histone acetylation, particularly at H3K123 and H3K80. ConclusionOur study demonstrates that SO exerts protective effects against SIMD through both GPR84-mediated anti-inflammatory and antioxidant actions and GPR84-independent enhancement of myocardial energy metabolism, possibly mediated by MCAD.

Mechanical circulatory support for sepsis-induced myocardial dysfunction

Mechanical circulatory support for sepsis-induced myocardial dysfunction

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.

GDF15 attenuates sepsis-induced myocardial dysfunction by inhibiting cardiomyocytes ferroptosis via the SOCS1/GPX4 signaling pathway

Sepsis is a systemic inflammatory response syndrome triggered by infection, presenting with symptoms such as fever, increased heart rate, and low blood pressure. In severe cases, it can lead to multiple organ dysfunction, posing a life-threatening risk. Sepsis-induced cardiomyopathy (SIC) is a critical factor in the poor prognosis of septic patients, leading to myocardial dysfunction characterized by cell death, inflammation, and diminished cardiac function. Ferroptosis, an iron-dependent form of programmed cell death, is a key mechanism causing cardiomyocyte damage in SIC. Growth differentiation factor 15 (GDF15), a member of the TGF-β superfamily, is associated with various cardiovascular diseases and can inhibit oxidative stress, reduce reactive oxygen species (ROS), and suppress ferroptosis. Elevated serum GDF15 levels in sepsis are correlated with organ injuries, suggesting its potential as a therapeutic target. However, its role and mechanisms in SIC remain unclear. Glutathione peroxidase 4 (GPX4), the only enzyme capable of reducing lipid peroxides within cells, protects cells by reducing lipid peroxidation levels and inhibiting ferroptosis. Investigating the regulatory factors of GPX4 may provide a theoretical basis for SIC treatment. In this study, a mouse SIC model revealed that elevated GDF15 exerts a protective effect. Antagonizing GDF15 exacerbates myocardial damage. Through transcriptomic analysis and other methods, we confirmed that GDF15 inhibits the expression of SOCS1 by activating the ALK5-SMAD2/3 pathway, thereby activates the JAK2/STAT3 pathway, promotes the transcription of GPX4, inhibits ferroptosis in cardiomyocytes, and plays a myocardial protective role in SIC.

Screening of novel disease genes of sepsis-induced myocardial Disfunction by RNA sequencing and bioinformatics analysis

BackgroundThere is still a lack of effective treatment for sepsis-induced myocardial dysfunction (SIMD), while the pathogenesis of SIMD still remains largely unexplained. MethodsRNA sequencing results (GSE267388 and GSE79962) were used for cross-species integrative analysis. Bioinformatic analyses were used to delve into function, tissue- and cell- specificity, and interactions of genes. External datasets and qRT-PCR experiments were used for validation. L1000 FWD was used to predict targeted drugs, and 3D structure files were used for molecular docking. ResultsBased on bioinformatic analyses, ten differentially expressed genes were selected as genes of interest, seven of which were verified to be significantly differential expression. Bucladesine was considered as a potential targeted drug for SIMD, which banded to seven target proteins primarily by forming hydrogen bonds. ConclusionIt was considered that Cebpd, Timp1, Pnp, Osmr, Tgm2, Cp, and Asb2 were novel disease genes, while bucladesine was a potential therapeutic drug, of SIMD.

Research Progress on Mechanisms and Treatment of Sepsis-Induced Myocardial Dysfunction.

Sepsis is a syndrome of organ dysfunction caused by a dysregulated immune response to infection, with high morbidity and mortality. At present, there have been many advances in the study of its pathogenesis, especially the cardiac dysfunction caused by sepsis, namely sepsis-induced myocardial dysfunction, SIMD, which has received widespread attention. The mechanisms of SIMD mainly include excessive release of inflammatory mediators, impaired mitochondrial function, autophagy, apoptosis and myocardial dysfunction. This article reviews the pathogenesis of SIMD and elaborates on the progress in its treatment, aiming to improve the prognosis of patients with SIMD and sepsis.

The Protective Effects of Ruscogenin Against Lipopolysaccharide-Induced Myocardial Injury in Septic Mice.

Sepsis-induced myocardial dysfunction commonly occurs in individuals with sepsis and is a severe complication with high morbidity and mortality rates. This study aimed to investigate the effects and potential mechanisms of the natural steroidal sapogenin ruscogenin (RUS) against lipopolysaccharide (LPS)-induced myocardial injury in septic mice. We found that RUS effectively alleviated myocardial pathological damage, normalized cardiac function, and increased survival in septic mice. RNA sequencing demonstrated that RUS administration significantly inhibited the activation of the NOD-like receptor signaling pathway in the myocardial tissues of septic mice. Subsequent experiments further confirmed that RUS suppressed myocardial inflammation and pyroptosis during sepsis. In addition, cultured HL-1 cardiomyocytes were challenged with LPS, and we observed that RUS could protect these cells against LPS-induced cytotoxicity by suppressing inflammation and pyroptosis. Notably, both the in vivo and in vitro findings indicated that RUS inhibited NOD-like receptor protein-3 (NLRP3) upregulation in cardiomyocytes stimulated with LPS. As expected, knockdown of NLRP3 blocked the LPS-induced activation of inflammation and pyroptosis in HL-1 cells. Furthermore, the cardioprotective effects of RUS on HL-1 cells under LPS stimulation were abolished by the novel NLRP3 agonist BMS-986299. Taken together, our results suggest that RUS can alleviate myocardial injury during sepsis, at least in part by suppressing NLRP3-mediated inflammation and pyroptosis, highlighting the potential of this molecule as a promising candidate for sepsis-induced myocardial dysfunction therapy.

Diagnostic and Predictive Value of LncRNA MCM3AP-AS1 in Sepsis and Its Regulatory Role in Sepsis-Induced Myocardial Dysfunction.

The present study focused on exploring the clinical value and molecular mechanism of LncRNA MCM3AP antisense RNA 1 (MCM3AP-AS1) in sepsis and sepsis-induced myocardial dysfunction (SIMD). 122 sepsis patients and 90 healthy were included. Sepsis patients were categorized into SIMD and non-MD. The expression levels of MCM3AP-AS1 and miRNA were examined using RT-qPCR. Diagnostic value of MCM3AP-AS1 in sepsis assessed by ROC curves. Logistic regression to explore risk factors influencing the occurrence of SIMD. Cardiomyocytes were induced by LPS to construct cell models in vitro. CCK-8, flow cytometry, and ELISA to analyze cell viability, apoptosis, and inflammation levels. Serum MCM3AP-AS1 was upregulated in patients with sepsis. The sensitivity and specificity of MCM3AP-AS1 were 75.41% and 93.33%, for recognizing sepsis from healthy controls. Additionally, elevated MCM3AP-AS1 is a risk factor for SIMD and can predict SIMD development. Compared with the LPS-induced cardiomyocytes, inhibition of MCM3AP-AS1 significantly attenuated LPS-induced apoptosis and inflammation; however, this attenuation was partially reversed by lowered miR-28-5p, but this reversal was partially eliminated by CASP2. MCM3AP-AS1 may be a novel diagnostic biomarker for sepsis and can predict the development of SIMD. MCM3AP-AS1 probably participated in SIMD progression by regulating cardiomyocyte inflammation and apoptosis through the target miR-28-5p/CASP2 axis.

Long Noncoding RNA SOX2OT Ameliorates Sepsis-Induced Myocardial Injury by Inhibiting Cellular Pyroptosis Through Mediating the EZH2/Nrf-2/NLRP3 Signaling Pathway.

Cellular pyroptosis is a pro-inflammatory mode of programmed cell death that has been identified in recent years, and studies have shown that the LncRNA SOX2OT regulates myocardial injury during sepsis, but the exact regulatory mechanism is unclear. The aim of this study was to assess the role of SOX2OT in regulating cardiomyocyte injury during sepsis cardiomyopathy. Rat cardiomyocytes, C57BL/6 mice, and transgenic mice were divided into four groups: control, LPS, LPS+ knockout LncRNA SOX2OT, and LPS+ overexpression LncRNA SOX2OT. Inflammatory factor levels were detected by qPCR. Associated proteins and gene expression were detected by Western blotting and qPCR. Dual luciferase was used to detect the target genes of SOX2OT. Nrf2 and EZH2 knockdown and overexpression cell lines were established, and the expression of related genes was detected by qPCR. Results In this study, we found that SOX2OT knockdown exacerbated LPS-induced levels of inflammatory factors and procalcitoninogen (PCT), and increased the expression of pyroptosis-related proteins and LDH. The results of dual luciferase reporter gene assay showed that EZH2 is the target gene of SOX2OT, and overexpression of SOX2OT decreased the expression of EZH2; we also found that knockdown of EZH2 in H9c2 cells decreased the expression of Nrf2, which was positively correlated with the expression level of NLRP3. Further in vivo results showed that overexpression of SOX2OT attenuated SIMD (sepsis-induced myocardial dysfunction), as evidenced by improved myocardial structural integrity and reduced inflammatory cell infiltration. The expression of pyroptosis-related proteins and LDH was significantly increased in the mice in the LPS group; this effect was reversed by overexpression of SOX2OT, and potentiated by knockdown of SOX2OT. Our data reveal a novel mechanism by which SOX2OT inhibits cardiomyocyte sepsis through the EZH2/Nrf-2/NLRP3 pathway, thereby attenuating septic myocardial injury, which may contribute to the development of new therapeutic strategies.

N6-Methyladenosine Demethylase ALKBH5 Promotes Pyroptosis by Modulating PTBP1 mRNA Stability in LPS-Induced Myocardial Dysfunction.

This study aims to investigate the mechanism by which alkB homolog 5 (ALKBH5) regulates polypyrimidine tract-binding protein 1 (PTBP1) to mediate cardiomyocyte pyroptosis in sepsis-induced myocardial injury. Lipopolysaccharide (LPS)-exposed H9C2 cell and rat models were established to mimic septic myocardial injury both in vitro and in vivo. The mRNA and protein levels of ALKBH5 and PTBP1 in the LPS-induced cell and septic rat models were detected. CCK-8 and flow cytometry were applied to detect cell viability and pyroptosis. H&E staining was used to observe myocardial tissue damage in rats, and immunohistochemistry to analyze the expression of pyroptosis and inflammation-related proteins in rat tissues. Elevated expressions of both ALKBH5 and PTBP1 were found in the myocardial tissues of LPS-induced septic rats. ALKBH5 knockdown could restore the cell viability and cell pyroptosis inhibited by LPS, while ALKBH5 promoted PTBP1 mRNA stability by affecting its N6-methyladenosine (m6A) modification. In vivo experiments showed that PTBP1 knockdown could largely reverse the antiproliferative and pro-pyroptosis effects of ALKBH5 in LPS-exposed H9C2 cells. ALKBH5 knockdown in in vivo experiments was found to suppress the expressions of pyroptosis biomarkers and attenuate myocardial injury in septic rats. ALKBH5 promoted mRNA stability and the expression of PTBP1 through m6A modification to induce pyroptosis in cardiomyocytes and ultimately aggravate sepsis-induced myocardial dysfunction.

Pretreatment with interleukin-15 attenuates inflammation and apoptosis by inhibiting NF-κB signaling in sepsis-induced myocardial dysfunction.

Sepsis-induced myocardial dysfunction (SIMD) is associated with poor prognosis and increased mortality in patients with sepsis. Cytokines are important regulators of both the initiation and progression of sepsis. Interleukin-15 (IL-15), a pro-inflammatory cytokine, has been linked to protective effects against myocardial infarction and myocarditis. However, the role of IL-15 in SIMD remains unclear. We established a mouse model of SIMD via cecal ligation puncture (CLP) surgery and a cell model of myocardial injury via lipopolysaccharide (LPS) stimulation. IL-15 expression was prominently upregulated in septic hearts as well as cardiomyocytes challenged with LPS. IL-15 pretreatment attenuated cardiac inflammation and cell apoptosis and improved cardiac function in the CLP model. Similar cardioprotective effects of IL-15 pretreatment were observed in vitro. As expected, IL-15 knockdown had the opposite effect on LPS-stimulated cardiomyocytes. Mechanistically, we found that IL-15 pretreatment reduced the expression of the pro-apoptotic proteins cleaved caspase-3 and Bax and upregulated the anti-apoptotic protein Bcl-2. RNA sequencing and Western blotting further confirmed that IL-15 pretreatment suppressed the activation of nuclear factor kappa B (NF-κB) signaling in mice with sepsis. Besides, the addition of NF-κB inhibitor can significantly attenuate cardiomyocyte apoptosis compared to the control findings. Our results suggest that IL-15 pretreatment attenuated the cardiac inflammatory responses and reduced cardiomyocyte apoptosis by partially inhibiting NF-κB signaling in vivo and in vitro, thereby improving cardiac function in mice with sepsis. These findings highlight a promising therapeutic strategy for SIMD.

Identification of 18β-glycyrrhetinic acid as an AGT inhibitor against LPS-induced myocardial dysfunction via high throughput screening

Sepsis induced myocardial dysfunction (SIMD) is a serious complication of sepsis. There is increasing evidence that the renin-angiotensin system (RAS) is activated in SIMD. Angiotensinogen (AGT) is a precursor of the RAS, and the inhibition of AGT may have significant cardiovascular benefits. But until now, there have been no reports of small molecule drugs targeting AGT. In this study, we designed a promoter-luciferase based system to screen for novel AGT inhibitors to alleviate SIMD. As a result of high-throughput screening, a total of 5 compounds from 351 medicinal herb‐derived natural compounds were found inhibiting AGT. 18β-glycyrrhetinic acid (18βGA) was further identified as a potent suppressor of AGT. In vitro experiments, 18βGA could inhibit the secretion of AGT by HepG2 cells and alleviate the elevated level of mitochondrial oxidative stress in cardiomyocytes co-cultured with HepG2 supernatants. In vivo, 18βGA prolonged the survival rate of SIMD mice, enhanced cardiac function, and inhibited the damage of mitochondrial function and inflammation. In addition, the results showed that 18βGA may reduce AGT transcription by downregulating hepatocyte nuclear factor 4 (HNF4) and that further alleviated SIMD. In conclusion, we provided a more efficient screening strategy for AGT inhibitors and expanded the novel role of 18βGA as a promising lead compound in rescuing cardiovascular disease associated with RAS overactivation.

Epigallocatechin-3-gallate protects sepsis‐induced myocardial dysfunction by inhibiting the nuclear factor-κB signaling pathway

Sepsis-induced myocardial dysfunction (SIMD) has become one of the most lethal complications of sepsis, while the treatment was limited by a shortage of pertinent drugs. Epigallocatechin-3-gallate (EGCG) is the highest content of active substances in green tea, and its application in cardiovascular diseases has broad prospects. This study was conducted to test the hypothesis that EGCG was able to inhibit lipopolysaccharide (LPS) induced myocardial dysfunction and investigate the underlying molecular mechanisms. The cardiac systolic function was assessed by echocardiography. The cardiomyocyte apoptosis was determined by TUNEL staining. The expression of inflammatory factors and apoptosis-related protein, cardiac markers were examined by Western Blot and qRT-PCR. EGCG effectively improve LPS-induced cardiac function damage, enhance left ventricular systolic function, and restore myocardial cell vitality. It can effectively inhibit the upregulation of TLR4 expression induced by LPS and inhibit IκB α/NF- κB/p65 signaling pathway, thereby inhibiting cardiomyocyte apoptosis and improving myocarditis. In conclusion, EGCG protects against SIMD through anti-inflammatory and anti-apoptosis effects; it was mediated by the inhibition of the TLR4/NF-κB signal pathway. Our results demonstrated that EGCG might be a possible medicine for SIMD prevention and treatment.

Meta-analysis of initial natriuretic peptides in the setting of sepsis-induced myocardial dysfunction.

Aim: To investigate the association of initial brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) with the detection of sepsis-induced myocardial dysfunction (SIMD) in the setting of Sepsis 3.0. Methods: Three databases were searched to analyze initial BNP and NT-proBNP levels between SIMD and non-SIMD groups. Results: Eighteen studies were included, most of which defined SIMD based on echocardiography. The SIMD group exhibited higher initial BNP and NT-proBNP levels in blood. NT-proBNP higher than a certain cutoff value (>3000pg/ml) was an independent risk factor for SIMD and its accuracy for SIMD diagnosis was moderate (pooled area under the curve: 0.81). Conclusion: Initial blood BNP and NT-proBNP levels are useful to assist in the detection of SIMD and further studies are warranted to determine the SIMD definition.

Septic Cardiomyopathy.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis-induced myocardial dysfunction represents reversible myocardial dysfunction which ultimately results in left ventricular dilatation or both, with consequent loss of contractility. Studies on septic cardiomyopathy report a wide range of prevalence ranging from 10% to 70%. Myocardial damage occurs as a result of weakened myocardial circulation, direct myocardial depression, and mitochondrial dysfunction. Mitochondrial dysfunction is the leading problem in the development of septic cardiomyopathy and includes oxidative phosphorylation, production of reactive oxygen radicals, reprogramming of energy metabolism, and mitophagy. Echocardiography provides several possibilities for the diagnosis of septic cardiomyopathy. Systolic and diastolic dysfunction of left ventricular is present in 50-60% of patients with sepsis. Right ventricular dysfunction is present in 50-55% of cases, while isolated right ventricular dysfunction is present in 47% of cases. Left ventricle (LV) diastolic dysfunction is very common in septic shock, and it represents an early biomarker, it has prognostic significance. Right ventricular dysfunction associated with sepsis patients with worse early prognosis. Global longitudinal stress and magnetic resonance imaging (MRI) of the heart are sufficiently sensitive methods, but at the same time MRI of the heart is difficult to access in intensive care units, especially when dealing with critically ill patients. Previous research has identified two biomarkers as a result of the integrated mitochondrial response to stress, and these are fibroblast growth factor-21 (FGF-21) and growth differentiation factor-15 (GDF-15). Both of the mentioned biomarkers can be easily quantified in serum or plasma, but they are difficult to be specific in patients with multiple comorbidities. Mitochondrial dysfunction is also associated with reduced levels of miRNA (microRNA), some research showed significance of miRNA in sepsis-induced myocardial dysfunction, but further research is needed to determine the clinical significance of these molecules in septic cardiomyopathy. Therapeutic options in the treatment of septic cardiomyopathy are not specific, and include the optimization of hemodynamic parameters and the use of antibiotic thera-pies with targeted action. Future research aims to find mechanisms of targeted action on the initial mechanisms of the development of septic cardiomyopathy.