Diabetes-associated cardiac fibrosis: Cellular effectors, molecular mechanisms and therapeutic opportunities.
Both type 1 and type 2 diabetes are associated with cardiac fibrosis that may reduce myocardial compliance, contribute to the pathogenesis of heart failure, and trigger arrhythmic events. Diabetes-associated fibrosis is mediated by activated cardiac fibroblasts, but may also involve fibrogenic actions of macrophages, cardiomyocytes and vascular cells. The molecular basis responsible for cardiac fibrosis in diabetes remains poorly understood. Hyperglycemia directly activates a fibrogenic program, leading to accumulation of advanced glycation end-products (AGEs) that crosslink extracellular matrix proteins, and transduce fibrogenic signals through reactive oxygen species generation, or through activation of Receptor for AGEs (RAGE)-mediated pathways. Pro-inflammatory cytokines and chemokines may recruit fibrogenic leukocyte subsets in the cardiac interstitium. Activation of transforming growth factor-β/Smad signaling may activate fibroblasts inducing deposition of structural extracellular matrix proteins and matricellular macromolecules. Adipokines, endothelin-1 and the renin-angiotensin-aldosterone system have also been implicated in the diabetic myocardium. This manuscript reviews our current understanding of the cellular effectors and molecular pathways that mediate fibrosis in diabetes. Based on the pathophysiologic mechanism, we propose therapeutic interventions that may attenuate the diabetes-associated fibrotic response and discuss the challenges that may hamper clinical translation.
['Russo|Ilaria|I|', 'Frangogiannis|Nikolaos G|NG|']
D000818:Animals D003920:Diabetes Mellitus D058065:Diabetic Cardiomyopathies D004719:Endomyocardial Fibrosis D042783:Endothelial Cells D016326:Extracellular Matrix Proteins D005786:Gene Expression Regulation D017127:Glycation End Products, Advanced D006801:Humans D007004:Hypoglycemic Agents D008264:Macrophages D032383:Myocytes, Cardiac D000067759:Receptor for Advanced Glycation End Products D012084:Renin-Angiotensin System D015398:Signal Transduction D051785:Smad Proteins D016212:Transforming Growth Factor beta
Fibrosis Diabetes Heart failure Fibroblast Obesity