Melatonin relieves sepsis-induced myocardial injury via regulating JAK2/STAT3 signaling pathway

Zhen, Genshen; Wen, Liang; Jia, Hepeng; Zheng, Xi

doi:10.23736/s0026-4806.20.06626-4

Cited by 15 publications

(7 citation statements)

References 19 publications

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“…1 Approximately 25−50% of sepsis patients are reported to be diagnosed with a myocardial injury or cardiac dysfunction, regarded as important pathological signs for the poor prognosis of sepsis patients. 2,3 Sepsis-induced cardiomyopathy was first described in the 1980s 4 and defined as sepsis accompanied by decreased left ventricular ejection fraction (LVEF) and ventricular dilatation. 5 The main clinical characteristics of sepsis-induced cardiomyopathy include systolic dysfunction, such as impaired ventricular contractility and decreased LVEF and diastolic dysfunction, such as ventricular dilatation and reversible cardiac dysfunction.…”

Section: ■ Introductionmentioning

confidence: 99%

Dulaglutide Alleviates LPS-Induced Injury in Cardiomyocytes

Wang

Han

et al. 2021

ACS Omega

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Background and purpose: Sepsis is a severe infection-induced disease with multiple organ failure, and sepsis-induced cardiomyopathy is a fatal condition. Inflammatory response and oxidative stress are reported to be involved in the development of sepsis-induced cardiomyopathy. Dulaglutide is a novel antidiabetic agent that is currently reported to exert an anti-inflammatory effect. The present study aims to explore the potential protective property of dulaglutide on lipopolysaccharide (LPS)-induced injury on cardiomyocytes. Methods: LPS was used to induce an in vitro injury model on cardiomyocytes. The mitochondrial reactive oxygen species (ROS) level was detected using MitoSOX red, and reduced glutathione (GSH) was measured to evaluate the status of oxidative stress in H9c2 myocardial cells. The expressions of NADPH oxidase-1 (NOX-1) and inducible nitric oxidesynthase (iNOS) were determined using real-time PCR and western blot analysis. Real-time PCR and enzyme-linked immunosorbent assay (ELISA) were both used to detect the expressions and concentrations of tumor necrosis factor-α, interleukin-1β, interleukin-17, matrix metalloproteinase-2, and matrix metalloproteinase-9 in H9c2 myocardial cells, respectively. The production of nitric oxide (NO) was measured using the Griess reagent. The levels of creatine kinase isoenzyme-MB (CK-MB) and cardiac troponin I (cTnI) were detected using ELISA. Western blot was utilized to determine the expressions of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and p-NF-κB p65 in H9c2 myocardial cells in the nucleus. Results: First, dulaglutide ameliorated LPS-induced oxidative stress by suppressing the production of mitochondrial ROS and elevating the level of reduced GSH, as well as downregulating NOX-1. Second, the LPS-induced cardiomyocyte injury was alleviated by dulaglutide through downregulating CK-MB and cTnI, accompanied by inhibiting iNOS expression and NO production. Lastly, the production of inflammatory factors and upregulation of MMPs induced by LPS were both significantly reversed by dulaglutide through suppressing the TLR4/Myd88/NF-κB signaling pathway. Conclusions: Dulaglutide alleviated LPS-induced injury in cardiomyocytes by inhibiting inflammation and oxidative stress.

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Section: ■ Introductionmentioning

confidence: 99%

Dulaglutide Alleviates LPS-Induced Injury in Cardiomyocytes

Wang

Han

et al. 2021

ACS Omega

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“…STAT3 is the main downstream effector of IL-6 signaling. Zhang et al ( 31 ) and Zhen et al ( 11 ) show that melatonin and traditional Chinese medicine Oxymatrine relieve sepsis-induced myocardial injury and simultaneously inhibit STAT3 signaling. However, it is still not fully understood that whether STAT3 plays a direct role and the specific mechanisms by which STAT3 contributes to SIMD.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorylated STAT3 subsequently dimerizes, translocates to the nucleus, and regulates gene transcription ( 9 , 10 ). Recent study ( 11 ) shows that STAT3 is activated in SIMD. However, the specific function and regulatory mechanism of IL-6/STAT3 pathway in SIMD remains unclear.…”

Section: Introductionmentioning

confidence: 99%

IL-6/STAT3 Signaling Promotes Cardiac Dysfunction by Upregulating FUNDC1-Dependent Mitochondria-Associated Endoplasmic Reticulum Membranes Formation in Sepsis Mice

Jiang

Peng

Shi

et al. 2022

Front. Cardiovasc. Med.

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AimsCytokine storm is closely related to the initiation and progression of sepsis, and the level of IL-6 is positively correlated with mortality and organ dysfunction. Sepsis-induced myocardial dysfunction (SIMD) is one of the major complications. However, the role of the IL-6/STAT3 signaling in the SIMD remains unclear.Methods and ResultsSeptic mice were induced by intraperitoneal injection of LPS (10 mg/kg). Echocardiography, cytokines detection, and histologic examination showed that sepsis mice developed cardiac systolic and diastolic dysfunction, increase of inflammatory cytokines in serum, activated STAT3 and TLR4/NFκB pathway in heart, and raised myocardial apoptosis, which were attenuated by IL-6/STAT3 inhibitor, Bazedoxifene. In vitro, we found that LPS decreased cell viability in a concentration-dependent manner and activated STAT3. Western blot and immunofluorescence results indicated that STAT3 phosphorylation induced by LPS was inhibited by Bazedoxifene. Bazedoxifene also suppressed LPS-induced IL-6 transcription. sIL-6R caused LPS-induced p-STAT3 firstly decreased and then significantly increased. More importantly, we found STAT3-knockdown suppressed LPS-induced expression of FUNDC1, a protein located in mitochondria-associated endoplasmic reticulum membranes (MAMs). Overexpression of STAT3 led to an increase in FUNDC1 expression. Dual-luciferase reporter assay was used to confirm that STAT3 was a potential transcription factor for FUNDC1. Moreover, we showed that LPS increased MAMs formation and intracellular Ca2+ levels, enhanced the expression of Cav1.2 and RyR2, decreased mitochondrial membrane potential and intracellular ATP levels, and promoted mitochondrial fragmentation, the expression of mitophagy proteins and ROS production in H9c2 cells, which were reversed by knockdown of FUNDC1 and IL-6/STAT3 inhibitor including Bazedoxifene and Stattic.ConclusionsIL-6/STAT3 pathway plays a key role in LPS-induced myocardial dysfunction, through regulating the FUNDC1-associated MAMs formation and interfering the function of ER and mitochondria. IL-6/STAT3/FUNDC1 signaling could be a new therapeutic target for SIMD.

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“…209 Similarly, in septic myocardium, activation of the JAK2/STAT3 signaling pathway aggravates myocardial damage, which is attenuated by melatonin via inhibition of the JAK2/STAT3 signaling pathway. 210 In summary, although the effects of melatonin on the JAK2/STAT3 signaling pathway are different under specific circumstances, the main effects are to protect cells. SIRT3-dependent regulation is also a significant method in cardiomyocyte protection during MI/R.…”

Section: Mel Atonin Re Scue S C Ard I Omyo C Y Te S From Mi/r Inj Urymentioning

confidence: 99%

“…For example, the JAK2/STAT3 signaling pathway is activated by H 2 O 2 in endothelial cells, but the expression of caspase‐3 and Bax is also increased, the expression of Bcl‐2 is decreased, and melatonin reverses these changes 209 . Similarly, in septic myocardium, activation of the JAK2/STAT3 signaling pathway aggravates myocardial damage, which is attenuated by melatonin via inhibition of the JAK2/STAT3 signaling pathway 210 . In summary, although the effects of melatonin on the JAK2/STAT3 signaling pathway are different under specific circumstances, the main effects are to protect cells.…”

Section: Melatonin Rescues Cardiomyocytes From Mi/r Injurymentioning

confidence: 99%

New insights into the role of melatonin in diabetic cardiomyopathy

Huang

Luo

Zhong

et al. 2022

Pharmacology Res & Perspec

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Thirty years ago, the prevalence of diabetic patients was only onefourth the current prevalence. In fact, the current number of diabetic patients has soared to 1 diabetic patient in every 11 people globally. 1 Moreover, diabetes has become the ninth leading cause of death worldwide. According to statistics from the World Health Organization, as of 2000, the number of diabetes patients worldwide had exceeded 170 million, and it is still increasing at an extremely fast rate. It is predicted that the number of diabetic-related deaths will double between 2000 and 2030. 2 Among diabetic patients, type 2 diabetes mellitus (T2DM) is most common, accounting for approximately 90% of adult patients with diabetes. Unlike type 1 diabetes mellitus (T1DM), which is an autoimmune disease, the

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Melatonin relieves sepsis-induced myocardial injury via regulating JAK2/STAT3 signaling pathway

Cited by 15 publications

References 19 publications

Dulaglutide Alleviates LPS-Induced Injury in Cardiomyocytes

Dulaglutide Alleviates LPS-Induced Injury in Cardiomyocytes

IL-6/STAT3 Signaling Promotes Cardiac Dysfunction by Upregulating FUNDC1-Dependent Mitochondria-Associated Endoplasmic Reticulum Membranes Formation in Sepsis Mice

New insights into the role of melatonin in diabetic cardiomyopathy

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