Heme Oxygenase-1 in Macrophages Drives Septic Cardiac Dysfunction via Suppressing Lysosomal Degradation of Inducible Nitric Oxide Synthase

Liu, Jia; Wang, Yaping; Wang, Yidong; Ma, Yuankun; Shen, Jian; Fu, Zurong; Wu, Yue; Su, Sheng-an; Zhang, Yuhao; Cai, Zhejun; Wang, Jianan; Xiang, Meixiang

doi:10.1161/circresaha.118.312910

Cited by 48 publications

(41 citation statements)

References 39 publications

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“…Administration of related metabolite cytoflavin was shown to be cardioprotective in doxorubicin-induced cardiomyopathy in rats 52 . Therefore, there is pre-clinical evidence that FMN is reduced in ischaemic myocardium, and that administration of FMN and/or related metabolites is cardioprotective in cardiac ischaemia and toxic cardiomyopathy [50][51][52][53] . However, we are the first to show a decrease in FMN in human heart failure myocardium.…”

Section: Discussionmentioning

confidence: 99%

Core functional nodes and sex-specific pathways in human ischaemic and dilated cardiomyopathy

Parker

Pearson

et al. 2020

Nat Commun

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Poor access to human left ventricular myocardium is a significant limitation in the study of heart failure (HF). Here, we utilise a carefully procured large human heart biobank of cryopreserved left ventricular myocardium to obtain direct molecular insights into ischaemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM), the most common causes of HF worldwide. We perform unbiased, deep proteomic and metabolomic analyses of 51 left ventricular (LV) samples from 44 cryopreserved human ICM and DCM hearts, compared to age-, gender-, and BMI-matched, histopathologically normal, donor controls. We report a dramatic reduction in serum amyloid A1 protein in ICM hearts, perturbed thyroid hormone signalling pathways and significant reductions in oxidoreductase co-factor riboflavin-5monophosphate and glycolytic intermediate fructose-6-phosphate in both; unveil genderspecific changes in HF, including nitric oxide-related arginine metabolism, mitochondrial substrates, and X chromosome-linked protein and metabolite changes; and provide an interactive online application as a publicly-available resource.

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Section: Discussionmentioning

confidence: 99%

Core functional nodes and sex-specific pathways in human ischaemic and dilated cardiomyopathy

Parker

Pearson

et al. 2020

Nat Commun

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“…LPS, which is mainly released by gram‐negative bacteria, is usually use to trigger a strong inflammatory process and induce sepsis . As an endotoxin, LPS can cause the excessive release of inflammatory factors such as IL‐1β, IL‐18, and TNF‐α …”

Section: Discussionmentioning

confidence: 99%

Ginsenoside Rg1 attenuates cardiomyocyte apoptosis and inflammation via the TLR4/NF‐kB/NLRP3 pathway

Luo

Yan

Sun

et al. 2019

J of Cellular Biochemistry

140

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Sepsis‐induced myocardial dysfunction (SIMD) causes high mortality in seriously ill patients. Ginsenoside Rg1 has been proven to have effective anti‐inflammatory and antiapoptotic properties. However, the specific role of Rg1 in SIMD and the molecular mechanism remain unclear. Hence, we aimed to investigate the latent effects of ginsenoside Rg1 against SIMD and explore its underlying mechanisms. Male C57BL/6J mice and neonatal rat cardiomyocytes (NRCMs) were used as in vivo and in vitro models, respectively. Western blot analysis was used to detect the level of protein expression, and reverse transcription polymerase chain reaction was conducted to determine the messenger RNA expression of inflammatory factors. The terminal deoxynucleotidyl transferase‐mediated nick end labeling assay and flow cytometry were used to determine the apoptosis rate. Echocardiography was performed to assess cardiac function. The results showed that Rg1 improved cardiac function and attenuated lipopolysaccharide (LPS)‐induced apoptosis and inflammation in mice. In addition, in NRCMs, Rg1 downregulated the expression of LPS‐induced inflammatory cytokines and reversed the increased expression of Toll‐like receptor 4 (TLR4), nuclear factor‐κB (NF‐κB), and NOD‐like receptor 3 (NLRP3). In addition, treatment with TLR4 small interfering RNA (siRNA), a p‐NF‐κB inhibitor, or NLRP3 siRNA suppressed LPS‐induced apoptosis and inflammation. In conclusion, Rg1 can attenuate LPS‐induced inflammation and apoptosis both in NRCMs and septic mice and restore impaired cardiac function. Moreover, Rg1 may exert its effect via blocking the TLR4/NF‐κB/NLRP3 pathway.

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“…The primers (GAPDH, TNF-α and IL-6) were designed and synthesized by Sangon Biotech (Shanghai, China). The forward and reverse primers of target genes are listed in Additional file 1: Table S1 [29][30][31].…”

Section: Detection Of Cardiac Tnf-α Il-6 Il-10 Tgf-β Inos and Argmentioning

confidence: 99%

Therapeutic efficacy of Schistosoma japonicum cystatin on sepsis-induced cardiomyopathy in a mouse model

Gao

Xie

et al. 2020

Parasites Vectors

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Background: Myocardial dysfunction is one of the most common complications of multiple organ failure in septic shock and significantly increases mortality in patients with sepsis. Although many studies having confirmed that helminthderived proteins have strong immunomodulatory functions and could treat inflammatory diseases, there is no report on the therapeutic effect of Schistosoma japonicum-produced cystatin (Sj-Cys) on sepsis-induced cardiac dysfunction. Methods: A model of sepsis-induced myocardial injury was established by cecal ligation and puncture (CLP) in mice. Upon CLP operation, each mouse was intraperitoneally treated with 10 µg of recombinant Sj-Cys (rSj-Cys). Twelve hours after CLP, the systolic and diastolic functions of the left ventricular were examined by echocardiography. The levels of myoglobin (Mb), cardiac troponin I (cTnI), N-terminal pro-Brain Natriuretic peptide (NT-proBNP) in sera, and the activity of myeloperoxidase (MPO) in cardiac tissues were examined as biomarkers for heart injury. The heart tissue was collected for checking pathological changes, macrophages and pro-inflammatory cytokine levels. To address the signaling pathway involved in the anti-inflammatory effects of rSj-Cys, myeloid differentiation factor 88 (MyD88) was determined in heart tissue of mice with sepsis and LPS-stimulated H9C2 cardiomyocytes. In addition, the therapeutic effects of rSj-Cys on LPS-induced cardiomyocyte apoptosis were also detected. The levels of M1 biomarker iNOS and M2 biomarker Arg-1 were detected in heart tissue. The pro-inflammatory cytokines TNF-α and IL-6, and regulatory cytokines IL-10 and TGF-β were measured in sera and their mRNA levels in heart tissue of rSj-Cys-treated mice. Results: After rSj-Cys treatment, the sepsis-induced heart malfunction was largely improved. The inflammation and injury of heart tissue were significantly alleviated, characterized as significantly decreased infiltration of inflammatory cells in cardiac tissues and fiber swelling, reduced levels of Mb, cTnI and NT-proBNP in sera, and MPO activity in heart tissue. The therapeutic efficacy of rSj-Cys is associated with downregulated pro-inflammatory cytokines (TNF-α and IL-6) and upregulated regulatory inflammatory cytokines (IL-10 and TGF-β), possibly through inhibiting the LPS-MyD88 signal pathway. Conclusions: RSj-Cys significantly reduced sepsis-induced cardiomyopathy and could be considered as a potential therapeutic agent for the prevention and treatment of sepsis associated cardiac dysfunction.

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Heme Oxygenase-1 in Macrophages Drives Septic Cardiac Dysfunction via Suppressing Lysosomal Degradation of Inducible Nitric Oxide Synthase

Abstract: Our results indicate that HO-1 in macrophages drives septic cardiac dysfunction. The mechanistic insights provide potential therapeutic targets to treat septic cardiac dysfunction.

Cited by 48 publications

References 39 publications

Core functional nodes and sex-specific pathways in human ischaemic and dilated cardiomyopathy

Core functional nodes and sex-specific pathways in human ischaemic and dilated cardiomyopathy

Ginsenoside Rg1 attenuates cardiomyocyte apoptosis and inflammation via the TLR4/NF‐kB/NLRP3 pathway

Therapeutic efficacy of Schistosoma japonicum cystatin on sepsis-induced cardiomyopathy in a mouse model

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