Abstract
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.
Highlights
Sepsis is defined as the dysregulated host response to infection contributing to life-threatening organ dysfunction [1]
We found that LPS remarkably decreased left ventricular ejection fraction (LVEF) (Figure 1B) and left ventricular fractional shortening (LVFS) (Figure 1C), and increased left ventricular internal dimensions at end systole (LVIDs) (Figure 1D) and LVESV (Figure 1F)
Bazedoxifene improved the impairment in systolic function induced by LPS, including LVEF, LVFS, LVIDs, LVIDd, LVESV, and LVEDV
Summary
Sepsis is defined as the dysregulated host response to infection contributing to life-threatening organ dysfunction [1]. Sepsisinduced myocardial dysfunction (SIMD) is one of the major complications in clinical sepsis, which contributes to systolic and diastolic dysfunction of heart [3, 4]. The mortality in sepsis patients with cardiac dysfunction is significantly higher than those without cardiac dysfunction (70–90% vs 20%) [5]. The serum cytokines of sepsis are significantly increased, including IL-6, IL-1β, and TNF-α [6]. Inflammatory reaction triggered by cytokines is the main cause of sepsis-induced multiple organ system failure [7]. The specific mechanism underlying the effect of cytokines on SIMD remains incompletely understood. Recent study [11] shows that STAT3 is activated in SIMD. The specific function and regulatory mechanism of IL-6/STAT3 pathway in SIMD remains unclear
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