期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 90, 期 -, 页码 84-93出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2015.12.011
关键词
Diabetes; Obesity; Fibrosis; Heart failure; Fibroblast
资金
- NIH [R01 HL76246, R01 HL85440]
- Fondazione Cassa di Risparmio di Lucca
- Fondazione Banca del Monte di Lucca
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL085440, R01HL076246] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK020541] Funding Source: NIH RePORTER
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-beta/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. (C) 2015 Elsevier Ltd. All rights reserved.
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