Fibrosis of the diabetic heart: Clinical significance, molecular mechanisms, and therapeutic opportunities

Abstract

In patients with diabetes, myocardial fibrosis may contribute to the pathogenesis of heart failure and arrhythmogenesis, increasing ventricular stiffness and delaying conduction. Diabetic myocardial fibrosis involves effects of hyperglycemia, lipotoxicity and insulin resistance on cardiac fibroblasts, directly resulting in increased matrix secretion, and activation of paracrine signaling in cardiomyocytes, immune and vascular cells, that release fibroblast-activating mediators. Neurohumoral pathways, cytokines, growth factors, oxidative stress, advanced glycation end-products (AGEs), and matricellular proteins have been implicated in diabetic fibrosis; however, the molecular links between the metabolic perturbations and activation of a fibrogenic program remain poorly understood. Although existing therapies using glucose- and lipid-lowering agents and neurohumoral inhibition may act in part by attenuating myocardial collagen deposition, specific therapies targeting the fibrotic response are lacking. This review manuscript discusses the clinical significance, molecular mechanisms and cell biology of diabetic cardiac fibrosis and proposes therapeutic targets that may attenuate the fibrotic response, preventing heart failure progression.

Keywords: Diabetes; Fibroblast; Fibrosis; Glucose-lowering agents; Heart failure; Hyperglycemia; Inflammation; Lipotoxicity; Oxidative stress.

Figure 1:. The effects of high glucose on cardiac fibroblast phenotype and function.

In vitro studies have suggested that exposure to high glucose has profound effects on fibroblast activation, survival, proliferation, responsiveness to growth factors (such as TGF-β), matrix-synthetic capacity, and matrix-remodeling properties. High glucose may also modulate fibroblast:matrix interactions by stimulating integrin synthesis. It should be emphasized that various studies have produced inconsistent findings, depending on the protocols used, the duration of glucose stimulation (acute vs. chronic), and the culture conditions. Although some studies have suggested that high glucose may promote myofibroblast conversion, in vivo investigations did not show significant myofibroblast conversion in diabetic hearts. coll-1 = collagen I, coll-III = collagen III, CTGF = Connective Tissue Growth Factor, FN = fibronectin, IL-1β = interleukin-1β, MMP-2 (−9) = matrix metalloproteinase-2 (−9), PDGF-β = platelet-derived growth factor-β, TGF-β = transforming growth factor-β.

Figure 2:. The Renin-Angiotensin-Aldosterone System (RAAS) in diabetes-associated cardiac fibrosis.

Diabetes-associated cardiac fibrosis involves both systemic and myocardial activation of the RAAS system. A: Systemic effects of the RAAS in diabetic myocardial fibrosis. Diabetes is associated with induction and activation of all components of the RAAS, including increased synthesis of angiotensinogen, accentuated renin release, increased activity of angiotensin converting enzyme (ACE) and chymase to generate angiotensin II, and enhanced aldosterone secretion by the adrenal cortex. Diabetes-associated activation of the RAAS results in volume overload (by increasing renal sodium reabsorption) and pressure overload (by inducing vasoconstriction and arterial fibrosis). These effects contribute indirectly to myocardial fibrosis. B: Local fibrogenic effects of Angiotensin II and aldosterone in the myocardium. Although systemic release of angiotensin II and angiotensin II-stimulated secretion of aldosterone are prominent in patients with diabetes, local myocardial expression of angiotensin II has also been reported. Angiotensin II and aldosterone directly activate fibroblasts (F), promoting their proliferation, increasing extracellular matrix (ECM) synthesis, and modulating the protease:antiprotease balance, thus regulating ECM remodeling. The fibrogenic actions of RAAS activation in the diabetic heart may also involve indirect effects on cardiomyocytes (CM) and macrophages (Ma) which, upon activation, may secrete fibrogenic cytokines and growth factors, stimulating fibroblast-derived matrix synthesis. Although effects of angiotensin II on endothelial to mesenchymal transition (EndMT) have been suggested, the endothelial origin of activated fibroblasts has not been convincingly documented in diabetic hearts. ACE = angiotensin converting enzyme, ADR = adrenal gland, ART = artery, AT1R = Angiotensin II receptor type 1, Erk = extracellular signal-regulated kinase, K = kidney, L = liver, miRs = microRNAs, MR = mineralocorticoid receptor, ROS = reactive oxygen species, TGF-β = transforming growth factor-β.