Astragaloside IV protects diabetic cardiomyopathy against inflammation and apoptosis via regulating TLR4/MyD88/NF-κB signaling pathway

Abstract Diabetic cardiomyopathy (DCM) is characterized by lipid accumulation, mitochondrial dysfunction, and aseptic inflammatory activation. Mitochondria-derived cytosolic DNA has been reported to induce inflammation by activating cyclic GMP-AMP synthase (cGAS)/the stimulator of interferon genes (STING) pathway in the adipose, liver, and kidney tissue. However, the role of cytosolic mtDNA in the progression of DCM is unclear. In this study, with an obesity-related DCM mouse model established by feeding db/db mice with a high-fat diet (HFD), we observed increased mtDNA in the cytosol and activated cGAS-STING signaling pathway during DCM, as well as the downstream targets, IRF3, NF-κB, IL-18, and IL-1β. In further study with a palmitic acid (PA)-induced lipotoxic cell model established in H9C2 cells, we revealed that the cytosolic mtDNA was resulted from PA-induced overproduction of mitochondrial ROS, which also led to the activation of the cGAS/STING system and its downstream targets. Notably, treatment of extracted mtDNA alone was sufficient to activate the cGAS-STING signaling pathway in cultured H9C2 cells. Besides, both knockdown of STING in PA-induced H9C2 cells and inhibition of STING by C-176 injection in the DCM mouse model could remarkably block the inflammation and apoptosis of cardiomyocytes. In conclusion, our study elucidated the critical role of cytosolic mtDNA-induced cGAS-STING activation in the pathogenesis of obesity-related DCM and provided preclinical validation for using a STING inhibitor as a new potential therapeutic strategy for the treatment of DCM.

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Melatonin protects against streptozotocin-induced diabetic cardiomyopathy through themammalian target of rapamycin (mTOR) signaling pathway

Advances in Clinical and Experimental Medicine ◽

10.17219/acem/103799 ◽

2019 ◽

Vol 28 (9) ◽

pp. 1171-1177 ◽

Cited By ~ 6

Author(s):

yasemin kandemir ◽

veysel tosun ◽

ünal güntekin

Keyword(s):

Signaling Pathway ◽

Diabetic Cardiomyopathy ◽

Mtor Signaling ◽

Target Of Rapamycin ◽

Mtor Signaling Pathway

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Advanced glycation end products facilitate proliferation and reduce early apoptosis of cardiac microvascular endothelial cell via PKCβ signaling pathway: insight from diabetic cardiomyopathy

The Anatolian Journal of Cardiology ◽

10.14744/anatoljcardiol.2019.21504 ◽

2019 ◽

Author(s):

Yi Luan

Keyword(s):

Endothelial Cell ◽

Signaling Pathway ◽

Diabetic Cardiomyopathy ◽

Advanced Glycation End Products ◽

Microvascular Endothelial Cell ◽

Advanced Glycation ◽

Glycation End Products ◽

End Products ◽

Early Apoptosis ◽

Cardiac Microvascular Endothelial Cell

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Astragaloside IV/lncRNA-TUG1/TRAF5 signaling pathway participates in podocyte apoptosis of diabetic nephropathy rats

Drug Design Development and Therapy ◽

10.2147/dddt.s166525 ◽

2018 ◽

Vol Volume 12 ◽

pp. 2785-2793 ◽

Cited By ~ 16

Author(s):

Xiao Lei ◽

Limei Zhang ◽

Zonglin Li ◽

Jigang Ren

Keyword(s):

Diabetic Nephropathy ◽

Signaling Pathway ◽

Astragaloside Iv ◽

Lncrna Tug1

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Abstract 26: Fibroblast Growth Factor 21 Prevents Diabetic Cardiomyopathy by Attenuating Cardiac Lipotoxicity via Erk1/2-dependent Signaling Pathway in Mice

Circulation Research ◽

10.1161/res.117.suppl_1.26 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Yi Tan ◽

Chi Zhang ◽

Xiaoqing Yan ◽

Zhifeng Huang ◽

Junlian Gu ◽

...

Keyword(s):

Cell Death ◽

Type 1 Diabetes ◽

Signaling Pathway ◽

P38 Mapk ◽

Diabetic Cardiomyopathy ◽

Cardiac Cell ◽

Diabetic Mice ◽

Ampk Signaling

The role of FGF21 plays in the development and progression of diabetic cardiomyopathy (DCM) has not been addressed. Here we demonstrated that type 1 diabetes decreased FGF21 levels in the blood, but up-regulated cardiac fgf21 expression about 40 fold at 2 months and 3-1.5 fold at 4 and 6 months after diabetes, which indicated a cardiac specific FGF21 adaptive up-regulation. To define the critical role of FGF21 in DCM, type 1 diabetes was induced in FGF21 knock out (FGF21KO) mice. At 1, 2 and 4 months after diabetes onset, no significant differences between FGF21KO and wild type (WT) diabetic mice in blood glucose and triglyceride levels were observed. But FGF21KO diabetic mice showed earlier and more severe cardiac dysfunction, remodeling and oxidative stress, as well as greater increase in cardiac lipid accumulation than WT diabetic mice. Mechanistically, FGF21 reduced palmitate-induced cardiac cell death, which was accompanied by up-regulation of cardiac Erk1/2, p38 MAPK and AMPK phosphorylation. Inhibition of each kinase with its inhibitor and/ or siRNA revealed that FGF21 prevents palmitate-induced cardiac cell death via up-regulating the Erk1/2-dependent p38 MAPK/AMPK signaling pathway. In vivo administration of FGF21, but not FGF21 plus ERK1/2 inhibitor, to diabetic mice significantly prevented cardiac cell death and reduced inactivation of Erk1/2, p38 MAPK and AMPK, and prevented cardiac remodeling and dysfunction at late-stage. Our results demonstrate that cardiac FGF21 decompensation may contribute to the development of DCM and FGF21 may be a therapeutic target for the treatment of diabetic cardiac damage via activation of Erk1/2-P38 MAPK-AMPK signaling.

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Kir6.1 improves cardiac dysfunction in diabetic cardiomyopathy via the AKT-Foxo1 signaling pathway

10.21203/rs.3.rs-33214/v1 ◽

2020 ◽

Author(s):

Jinxin Wang ◽

Jing Bai ◽

Peng Duan ◽

Hao Wang ◽

Yang Li ◽

...

Keyword(s):

Cardiac Function ◽

Signaling Pathway ◽

Diabetic Cardiomyopathy ◽

Cardiac Dysfunction ◽

Diabetic Patients ◽

Protein Levels ◽

Inwardly Rectifying Potassium Channel ◽

Transmission Electron ◽

Hematoxylin And Eosin ◽

And Function

Abstract Background: Diabetic cardiomyopathy (DCM) severely impairs the health of diabetic patients. Previous studies have shown that the expression of inwardly rectifying potassium channel 6.1 (Kir6.1) in heart mitochondria is significantly reduced in type 1 diabetes. However, whether its expression and function are changed and what role it plays in type 2 DCM have not been reported. This study investigated the role and mechanism of Kir6.1 in DCM.Methods: The cardiac function in mice was analyzed by echocardiography, ELISA, hematoxylin and eosin staining, TUNEL and transmission electron microscopy. The mitochondrial function in cardiomyocytes was measured by the oxygen consumption rate and the mitochondrial membrane potential (ΔΨm). Kir6.1 expression at the mRNA and protein levels was analyzed by quantitative real-time PCR and western blotting (WB), respectively. The protein expression of t-AKT, p-AKT, t-Foxo1, and p-Foxo1 was analyzed by WB.Results: We found that the cardiac function and the Kir6.1 expression in DCM mice were decreased. Kir6.1 overexpression improved cardiac dysfunction and upregulated the phosphorylation of AKT and Foxo1 in the DCM mouse model. Furthermore, Kir6.1 overexpression also improved cardiomyocyte dysfunction and upregulated the phosphorylation of AKT and Foxo1 in cardiomyocytes with insulin resistance. In contrast, cardiac-specific Kir6.1 knockout aggravated the cardiac dysfunction and downregulated the phosphorylation of AKT and Foxo1 in DCM mice. Furthermore, Foxo1 activation downregulated the expression of Kir6.1 and decreased the ΔΨm in cardiomyocytes. In contrast, Foxo1 inactivation upregulated the expression of Kir6.1 and increased the ΔΨm in cardiomyocytes. Chromatin immunoprecipitation assay demonstrated that the Kir6.1 promoter region contains a functional Foxo1-binding site .Conclusions: Kir6.1 improves cardiac dysfunction in DCM, probably through the AKT-Foxo1 signaling pathway. Moreover, the crosstalk between Kir6.1 and the AKT-Foxo1 signaling pathway may provide new strategies for reversing the defective signaling in DCM.

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