Reduced silent information regulator 1 signaling exacerbates sepsis-induced myocardial injury and mitigates the protective effect of a liver X receptor agonist

Han, Dongyi; Li, Xiang; Li, Shuang; Su, Tao; Fan, Li; Fan, Wensi; Qiao, Hongyu; Chen, Jiangwei; Fan, Min; Li, Xiujuan; Wang, Yabin; Ma, Sai; Qiu, Ya; Tian, Zuhong; Cao, Feng

doi:10.1016/j.freeradbiomed.2017.10.005

Cited by 67 publications

(38 citation statements)

References 73 publications

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“…Echocardiographic results demonstrated that the CLP-induced sepsis resulted in a significant decrease in left ventricular EF, FS and E/A ratio, indicating the serious damage on heart systolic and diastolic functions. In addition, the levels of cTnI, NT-proBNP and Mb in sera and the MPO level in heart tissue are the important biochemical markers of cardiac damage and injury in early septic shock [32,33,48,49]. The CLP-induced sepsis model established in this study demonstrated significantly increased levels of cTnI, NT-proBNP and Mb in sera and a high level of MPO in heart tissue, indicating that the heart tissue and cells were seriously damaged as a result of the CLP-induced sepsis.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…M‐mode echocardiography was accomplished with an echocardiography system with a 15‐MHz linear transducer (Vevo 2100; VisualSonics, Canada) as we previously described . Left ventricular systolic pressure (LVSP), left ventricular end‐diastolic pressure (LVEDP), and the maximal rates of increase and decrease in LV pressure (+dP/dtmax and ‐dP/dtmax) during the cardiac cycle were measured using a Millar pressure catheter as we previously described …”

Section: Methodsmentioning

confidence: 99%

Activation of melatonin receptor 2 but not melatonin receptor 1 mediates melatonin‐conferred cardioprotection against myocardial ischemia/reperfusion injury

Han

Wang

Chen

et al. 2019

Journal of Pineal Research

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Accumulated pieces of evidence have proved the beneficial effects of melatonin on myocardial ischemia/reperfusion (MI/R) injury, and these effects were largely dependent on melatonin membrane receptor activation. In humans and other mammals, there are two types of melatonin receptors, including the melatonin receptor 1 (MT1, melatonin receptor 1a or MTNR1A) and melatonin receptor 1 (MT2, melatonin receptor 1b or MTNR1B) receptor subtypes. However, which receptor mediates melatonin‐conferred cardioprotection remains unclear. In this study, we employed both loss‐of‐function and gain‐of‐function approaches to reveal the answer. Mice (wild‐type; MT1 or MT2 silencing by in vivo minicircle vector; and those overexpressing MT1 or MT2 by in vivo AAV9 vector) were exposed to MI/R injury. Both MT1 and MT2 were present in wild‐type myocardium. MT2, but not MT1, was essentially upregulated after MI/R Melatonin administration significantly reduced myocardial injury and improved cardiac function after MI/R Mechanistically, melatonin treatment suppressed MI/R‐initiated myocardial oxidative stress and nitrative stress, alleviated endoplasmic reticulum stress and mitochondrial injury, and inhibited myocardial apoptosis. These beneficial actions of melatonin were absent in MT2‐silenced heart, but not the MT1 subtype. Furthermore, AAV9‐mediated cardiomyocyte‐specific overexpression of MT2, but not MT1, mitigated MI/R injury and improved cardiac dysfunction, which was accompanied by significant amelioration of oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction. Mechanistically, MT2 protected primary cardiomyocytes against hypoxia/reoxygenation injury via MT2/Notch1/Hes1/RORα signaling. Our study presents the first direct evidence that the MT2 subtype, but not MT1, is a novel endogenous cardiac protective receptor against MI/R injury. Medications specifically targeting MT2 may hold promise in fighting ischemic heart disease.

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“…Although several studies have pointed out that the immunosuppression occurring in late stages of sepsis is the primary reason for mortality, the cytokine storm and cardiac dysfunction occurring in the early onset of sepsis are also essential causes of organ dysfunction and mortality of septic patients ( Hotchkiss et al, 2013 ). Septic cardiac dysfunction has been associated with excessive production of cytokines, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and high-mobility group box-1 (HMGB1), which also contribute to myocyte apoptosis and damages ( Buerke et al, 2008 ; Wang et al, 2014 ; Zhang et al, 2015 ; Han et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Qiang-Xin 1 Formula Prevents Sepsis-Induced Apoptosis in Murine Cardiomyocytes by Suppressing Endoplasmic Reticulum- and Mitochondria-Associated Pathways

Liu

et al. 2018

Front. Pharmacol.

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Sepsis is reported to be an unusual systemic reaction to infection, accompanied by multiple-organ failure. Sepsis-induced cardiomyopathy (SIC), defined as damages and dysfunction of the heart, is essential in the pathogenesis of sepsis. Traditional Chinese formula, which has long been used to improve the situation of patients through multitarget regulation, is now gradually being used as complementary therapy. The present study aimed to investigate the effect of Qiang-Xin 1 (QX1) formula, a traditional Chinese herbal medicine designed for cardiac dysfunction, on cecal ligation puncture (CLP)-induced heart damage and its underlying mechanisms in mice. Survival test first showed that an oral administration of QX1 formula significantly increased the 7-days survival of septic mice from 22 to 40%. By estimating the secretion of serum cytokines, QX1 treatment dramatically inhibited the excessive production of interleukin-1β and tumor necrosis factor-α. Immunohistochemical staining illustrated that the expression of c-Jun N-terminal kinase, caspase-12, and high-mobility group box 1 was downregulated in cardiomyocytes of the QX1-treated group compared with that of the CLP surgery group. Western blotting confirmed that the activation of essential caspase family members, such as caspase-3, caspase-9, and caspase-12, was prohibited by treatment with QX1. Moreover, the abnormal expression of key regulators of endoplasmic reticulum (ER) and mitochondria-associated apoptosis in cardiomyocytes of septic mice, including CHOP, GRP78, Cyt-c, Bcl-2, Bcl-XL, and Bax, was effectively reversed by treatment with QX1 formula. This study provided a new insight into the role of QX1 formula in heart damage and potential complementary therapeutic effect of traditional Chinese medicine on sepsis.

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Reduced silent information regulator 1 signaling exacerbates sepsis-induced myocardial injury and mitigates the protective effect of a liver X receptor agonist

Cited by 67 publications

References 73 publications

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

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

Activation of melatonin receptor 2 but not melatonin receptor 1 mediates melatonin‐conferred cardioprotection against myocardial ischemia/reperfusion injury

Qiang-Xin 1 Formula Prevents Sepsis-Induced Apoptosis in Murine Cardiomyocytes by Suppressing Endoplasmic Reticulum- and Mitochondria-Associated Pathways

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