Diabetes-associated cardiac fibrosis: Cellular effectors, molecular mechanisms and therapeutic opportunities

J Mol Cell Cardiol. 2016 Jan;90:84-93. doi: 10.1016/j.yjmcc.2015.12.011. Epub 2015 Dec 15.

Abstract

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.

Keywords: Diabetes; Fibroblast; Fibrosis; Heart failure; Obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Diabetes Mellitus / drug therapy
  • Diabetes Mellitus / genetics*
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / pathology
  • Diabetic Cardiomyopathies / drug therapy
  • Diabetic Cardiomyopathies / genetics*
  • Diabetic Cardiomyopathies / metabolism
  • Diabetic Cardiomyopathies / pathology
  • Endomyocardial Fibrosis / drug therapy
  • Endomyocardial Fibrosis / genetics*
  • Endomyocardial Fibrosis / metabolism
  • Endomyocardial Fibrosis / pathology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Extracellular Matrix Proteins / genetics*
  • Extracellular Matrix Proteins / metabolism
  • Gene Expression Regulation
  • Glycation End Products, Advanced / genetics*
  • Glycation End Products, Advanced / metabolism
  • Humans
  • Hypoglycemic Agents / therapeutic use
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / pathology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Receptor for Advanced Glycation End Products / genetics
  • Receptor for Advanced Glycation End Products / metabolism
  • Renin-Angiotensin System / drug effects
  • Signal Transduction
  • Smad Proteins / genetics
  • Smad Proteins / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism

Substances

  • AGER protein, human
  • Extracellular Matrix Proteins
  • Glycation End Products, Advanced
  • Hypoglycemic Agents
  • Receptor for Advanced Glycation End Products
  • Smad Proteins
  • Transforming Growth Factor beta