scholarly journals Diabetic Cardiomyopathy: The Case for a Role of Fructose in Disease Etiology

Diabetes ◽  
2016 ◽  
Vol 65 (12) ◽  
pp. 3521-3528 ◽  
Author(s):  
Lea M.D. Delbridge ◽  
Vicky L. Benson ◽  
Rebecca H. Ritchie ◽  
Kimberley M. Mellor
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Disease Etiology

scholarly journals Role of CCR2 in the Development of Streptozotocin-Treated Diabetic Cardiomyopathy

Diabetes ◽  
2019 ◽  
Vol 68 (11) ◽  
pp. 2063-2073 ◽  
Author(s):  
Xin Tan ◽  
Lizhi Hu ◽  
Zhiping Shu ◽  
Long Chen ◽  
Xiangrao Li ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy

scholarly journals Role of IL-17 and Th17 Cells in Liver Diseases

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Linda Hammerich ◽  
Felix Heymann ◽  
Frank Tacke
Keyword(s):  
Chemokine Receptors ◽  
Liver Diseases ◽  
Th17 Cells ◽  
Hepatic Inflammation ◽  
T Helper ◽  
Disease Etiology ◽  
Cell Recruitment ◽  
Cell Responses ◽  
Injured Liver

Unbalanced Th1/Th2 T-cell responses in the liver are a characteristic of hepatic inflammation and subsequent liver fibrosis. The recently discovered Th17 cells, a subtype of CD4+T-helper cells mainly producing IL-17 and IL-22, have initially been linked to host defense against infections and to autoimmunity. Their preferred differentiation upon TGFβand IL-6, two cytokines abundantly present in injured liver, makes a contribution of Th17 cells to hepatic inflammation very likely. Indeed, initial studies in humans revealed activated Th17 cells and Th17-related cytokines in various liver diseases. However, functional experiments in mouse models are not fully conclusive at present, and the pathogenic contribution of Th17 cells to liver inflammation might vary upon the disease etiology, for example, between infectious and autoimmune disorders. Understanding the chemokines and chemokine receptors promoting hepatic Th17 cell recruitment (possibly CCR6 or CCR4) might reveal new therapeutic targets interfering with Th17 migration or differentiation in liver disease.

scholarly journals Lipotoxicity-Induced mtDNA Release Promotes Diabetic Cardiomyopathy by Activating the cGAS-STING Pathway in Obesity Related Diabetes

2021 ◽  
Author(s):  
Xiu Mei Ma ◽  
Kang Geng ◽  
Betty Yuen-Kwan Law ◽  
Peng Wang ◽  
Yue Li Pu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Signaling Pathway ◽  
Diabetic Cardiomyopathy ◽  
Cell Model ◽  
Critical Role ◽  
Kidney Tissue ◽  
H9c2 Cells ◽  
Downstream Targets ◽  
Sting 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.

scholarly journals Diabetic cardiomyopathy and its mechanisms: Role of oxidative stress and damage

2014 ◽  
Vol 5 (6) ◽  
pp. 623-634 ◽  
Author(s):  
Quan Liu ◽  
Shudong Wang ◽  
Lu Cai
Keyword(s):  
Oxidative Stress ◽  
Diabetic Cardiomyopathy

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

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.

Role of AMP-activated protein kinase on cardio-metabolic abnormalities in the development of diabetic cardiomyopathy: A molecular landscape

2020 ◽  
Vol 888 ◽  
pp. 173376
Author(s):  
Abdul Haye ◽  
Mohd. Asif Ansari ◽  
Syed Obaidur Rahman ◽  
Yasmeen Shamsi ◽  
Danish Ahmed ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Diabetic Cardiomyopathy ◽  
Metabolic Abnormalities ◽  
Molecular Landscape ◽  
Amp Activated Protein Kinase

scholarly journals Exendin-4 Protects against Hyperglycemia-Induced Cardiomyocyte Pyroptosis via the AMPK-TXNIP Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Hong Wei ◽  
Rui Bu ◽  
Qinghui Yang ◽  
Jing Jia ◽  
Tao Li ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
High Fat Diet ◽  
Rna Silencing ◽  
Diabetic Heart ◽  
Cardiac Inflammation ◽  
Caspase 1 ◽  
Signaling Mechanisms ◽  
Patients With Diabetes ◽  
Cardiac Condition

Diabetic cardiomyopathy is a common cardiac condition in patients with diabetes mellitus, which results in cardiac hypertrophy and subsequent heart failure. Chronic inflammation in the diabetic heart results in loss of cardiomyocytes and subsequentially cardiac dysfunction. Accumulated evidence implicated pyroptosis as a vital contributor to the hyperglycemia-induced cardiac inflammatory response. Exendin-4, a GLP analog, promotes survival of cardiomyocytes in cardiovascular diseases, including diabetic cardiomyopathy. However, the role of Exendin-4 in cardiac pyroptosis remains to be elucidated. Our study revealed that Exendin-4 treatment protected against heart remolding and dysfunction and attenuated cardiac inflammation in high-fat diet-fed rats. The activity of caspase-1 and production of pyroptotic cytokines were significantly inhibited by Exendin-4 treatment in the diabetic heart and in high glucose-treated cardiomyocytes as well. In an effort to understand the signaling mechanisms underlying the antipyroptotic property of Exendin-4, we found that blockade of AMPK, an oxidative stress sensor, activity diminished the antipyroptotic property of Exendin-4. Phosphorylation of AMPK resulted in degeneration of TXNIP that promoted the activation of the NLRP3 inflammasome. Exendin-4 treatment decreased the protein level of TXNIP. Moreover, RNA silencing of TXNIP mimicked the antipyroptotic actions of Exendin-4. These findings promoted us to propose a new signaling pathway mediating cardioprotective effect of Exendin-4 under hyperglycemic conditions: Exendin-4 → ROS↓ → pAMPK↑ → TXNIP↓ → caspase-1↓ → IL-1β and IL-18↓ → pyroptosis↓. In general, our study identified Exendin-4 as a pyroptotic inhibitor protecting against hyperglycemia-induced cardiomyocyte pyroptosis via the AMPK-TXNIP pathway.

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