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

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.

β-Elemene Attenuates Renal Fibrosis in the Unilateral Ureteral Obstruction Model by Inhibition of STAT3 and Smad3 Signaling via Suppressing MyD88 Expression

“…STAT3 is a polymorphic transcription factor involved in a range of physiological and pathophysiological processes, including inflammation, cell growth, proliferation, and differentiation [ 20 , 21 , 22 , 23 ]. STAT3 has been shown to induce the expression of multiple fibrotic genes and can transduce the pro-fibrotic effects of TGF-β from the cell surface to the nucleus.…”

Beneficial Effects of O-GlcNAc Stimulation in a Young Rat Model of Sepsis: Beyond Modulation of Gene Expression

“…Reinforcing this observation, genes involved in the MAPK, mTOR, TLR2/MyD88 and JAK/STAT pathway are also up-regulated in the LPS group, as recently described in sepsis patients [ 26 ], confirming the pertinence of such approaches. JAK/STAT3 is a major pathway described as cardio-protective [ 27 , 28 ]; however, this pathway could also contribute to cardiac dysfunction [ 29 , 30 , 31 ], notably during septic shock [ 32 , 33 ]. Recent studies provide some evidence of therapeutic potential for targeting STAT3 in the cecal and ligature-puncture-induced sepsis model [ 34 , 35 ].…”

Endothelial Dysfunction and Diabetic Cardiomyopathy

“…Experimental evidence indicated increased mito-Ca 2+ uptake by pharmacological or genetic facilitation, improving cardiac systolic dysfunction. Reticulum-mitochondria Ca 2+ miscoupling disrupted mitochondrial bioenergetics and organelle Ca 2+ exchange, further damaging cell contraction ( 92 ). On the other hand, sustaining lipid accumulation and mitochondrial dysfunction induces ROS generation, which in turn leads to further impaired mitochondrial function and decreased FAO capacity, resulting in lipid accumulation, diastolic dysfunction and eventually heart failure.…”

“…Abnormal endothelial function induces the imbalance between components derived from endothelial cells. ET-1 stimulates the entry of extracellular Ca 2+ and activates the intracellular PLC/IP3/Ca 2+ pathway via cGMP-dependent pathway ( 92 ).…”