Fig. 1. Schematic illustrating the putative mechanisms leading to diabetic cardiomyopathy. Sustained hyperglycemia causes vascular endothelial cell dysfunction, resulting in increased permeability, reduced blood flow, and subsequently tissue ischemia. In response to tissue ischemia, endothelial cells release growth factors that increase basement membrane (BM) thickening and extracellular matrix (ECM) deposition. Growth factor and cytokine elaboration may also contribute to myocyte dysfunction and loss. In long-standing diabetes, this response is sustained and exacerbated, ultimately leading to diabetic cardiomyopathy and heart failure (ET-1, endothelin-1; NO, nitric oxide).

Fig. 2. Proposed mechanisms of endothelin (ET) alteration and functional consequences in cardiac endothelial cells and myocytes. High glucose-induced oxidative stress and other biochemical anomalies such as protein kinase C (PKC) activation, aldose reductase (AR) induction, and interaction of advanced glycation end-product (AGE) with their receptor (RAGE) can increase ET expression by endothelial cells. Altered ET levels may then lead to both hemodynamic (vasoconstriction/blood flow and permeability) and structural (extracellular matrix [ECM] deposition, myocyte hypertrophy) changes in the heart (NO, nitric oxide; NF-κB, nuclear factor-κB).

Fig. 3. Interaction between endothelin-1 (ET-1) and nitric oxide (NO) in endothelial-dependent impaired vasodilatation. Hyperglycemia-induced expression of ET and activation of protein kinase C (PKC) may regulate NO synthase (NOS) at both the transcriptional and the post-translational level. NOS-derived NO is sequestered by oxidative stress reducing NO availability and impairing vasodilatation and coronary flow reserve in diabetic cardiomyopathy.

Fig. 4. Schematic representation of possible mechanisms arbitrating hyperglycemia-induced oxidative stress. Hyperglycemia may regulate reactive oxygen species (ROS) production and oxidative stress by a number of mechanisms. Increased oxidative damage may be caused by alteration of key enzymes such as nitric oxide synthase (NOS), heme oxygenase (HO), and aldose reductase (AR). For example, increased NOS activity, superoxide production, and conversion of NO to peroxynitrite can contribute to oxidative damage. Increased AR activity may lead to decreased NADPH/NADP⁺ ratio and depletion of cofactors for anti-oxidant enzymes. Augmented HO activity may contribute to oxidative stress by increasing redox active iron accumulation in the heart tissues. Other contributing factors that increase oxidative stress include augmented glucose auto-oxidation, glucose flux through the mitochondrial electron transport chain (ETC), and interaction of advanced glycation end-products (AGE) with their receptors (RAGE) (O₂⁻, superoxide).

Therapeutic targets for diabetic cardiomyopathy

ATP, adenosine triphosphate; AGE, advanced glycation end-products; AR, aldose reductase; ET, endothelin; ECM, extracellular matrix; FFA, free fatty acid; HO, heme oxygenase; MAPK, mitogen-activated protein kinase; NO, nitric oxide; NF-κB, nuclear factor-κB; PPAR, peroxisome proliferator-activated receptor; PARP, poly (ADP-ribose) polymerase; PKB, protein kinase B; PKC, protein kinase C; SGK, serum- and glucocorticoid-regulated kinase.