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

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.

Figure 1

Cardiac fibrosis in experimental models of diabetes. A. db/db mice develop severe obesity and diabetes, associated with myocardial fibrosis. B–E. Sirius red staining labels collagen (red – arrows) in the cardiac interstitium (B) and in perivascular areas (C) in lean and db/db mice (D–E). db/db animals exhibit expansion of the interstitial space (D) and perivascular accumulation of collagen (E).

Figure 2

The cell biology of diabetes-associated cardiac fibrosis. Diabetes-associated hyperglycemia, generation of advanced glycation end-products (AGEs) and reactive oxygen species (ROS) and neurohumoral activation directly activate resident cardiac fibroblasts and may induce a proliferative response and a matrix-synthetic phenotype. Induction and activation of fibrogenic growth factors (such as TGF-β) may play an important role in fibroblast stimulation. Immune cells (monocytes/Mo, macrophages/Mac, lymphocytes/L and mast cells/MC) may contribute to the fibrotic response by secreting pro-fibrotic mediators. Cardiomyocytes (CM) and endothelial cells (EC) may also secrete growth factors and modulate fibroblast phenotype. Endothelial cells and pericytes may transdifferentiate into fibroblasts contributing to the expansion of the fibroblast population in diabetic hearts. Deposition of matricellular proteins (such as thrombospondin-1) in the diabetic myocardium may promote a pro-fibrotic phenotype in interstitial cells.