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

The cell biology of diabetic cardiac fibrosis. The primary metabolic perturbations of type 1 and type 2 diabetes, hypeglycemia and insulin resistance, activate cardiac fibroblasts, the main cellular effectors of cardiac fibrosis. In addition to their direct effects on cardiac fibroblasts, metabolic...
Ausführliche Beschreibung

The cell biology of diabetic cardiac fibrosis. The primary metabolic perturbations of type 1 and type 2 diabetes, hypeglycemia and insulin resistance, activate cardiac fibroblasts, the main cellular effectors of cardiac fibrosis. In addition to their direct effects on cardiac fibroblasts, metabolic changes may promote fibrosis through actions on other myocardial cell types, such as cardiomyocytes, immune cells and vascular cells. In the diabetic heart, cardiomyocytes may exhibit activation of oxidative pathways, resulting in release of fibrogenic cytokines and growth factors, and local activation of angiotensin II. Inflammatory stimulation may also induce Transforming Growth Factor-β (TGF-β) synthesis by cardiac macrophages and lymphocytes, whereas mast cells may secrete chymase, activating an alternative pathway involved in angiotensin II generation. Endothelial cells may contribute to the fibrotic response by producing fibrogenic growth factors and endothelin-1 (ET-1). In the diabetic heart, macrophages, vascular cells and fibroblasts may produce specialized matrix proteins with fibrogenic properties (such as fibronectin (FN) and thrombospondin-1 (TSP-1)). Although resident cardiac fibroblasts are the predominant matrix-producing cells in diabetic hearts, contributions of endothelial cells converting to fibroblasts through endothelial to mesenchymal transition (EndMT), and of mural cells that may acquire a fibroblast phenotype, have been suggested, but not convincingly documented. Increased deposition of interstitial and perivascular collagens and matrix crosslinking, increase myocardial stiffness and may play an important role in development of diastolic dysfunction, and in the pathogenesis of diabetes-associated heart failure with preserved ejection fraction (HFpEF). IL-1 = interleukin-1, ROS = reactive oxygen species, TNF-α = tumor necrosis factor-α. Ausführliche Beschreibung