Established and Emerging Mechanisms of Diabetic Cardiomyopathy

Abstract

Diabetes mellitus increases the risk for the development of heart failure even in the absence of coronary artery disease and hypertension, a cardiac entity termed diabetic cardiomyopathy (DC). Clinically, DC is increasingly recognized and typically characterized by concentric cardiac hypertrophy and diastolic dysfunction, ultimately resulting in heart failure with preserved ejection fraction (HFpEF) and potentially even heart failure with reduced ejection fraction (HFrEF). Numerous molecular mechanisms have been proposed to underlie the alterations in myocardial structure and function in DC, many of which show similar alterations in the failing heart. Well investigated and established mechanisms of DC include increased myocardial fibrosis, enhanced apoptosis, oxidative stress, impaired intracellular calcium handling, substrate metabolic alterations, and inflammation, among others. In addition, a number of novel mechanisms that receive increasing attention have been identified in recent years, including autophagy, dysregulation of microRNAs, epigenetic mechanisms, and alterations in mitochondrial protein acetylation, dynamics and quality control. This review aims to provide an overview and update of established underlying mechanisms of DC, as well as a discussion of recently identified and emerging mechanisms that may also contribute to the structural and functional alterations in DC.

Keywords: Diabetes mellitus; Diabetic cardiomyopathy; Heart failure.

Fig. 1. Consequences of diabetes-induced alterations in substrate metabolism and sources of increased ROS in DC. Increased FA uptake results in accumulation of TAG, lipid intermediates and increased FA oxidation, all of which may harm the cardiomyocyte. Increased glucose entry into the cardiomyocyte may promote alternative pathways of glucose utilization, thus provoking an increase in ROS, AGE, and O-GlcNAcylation. Increased amounts of intramitochondrial ROS may be generated by the electron transport chain, by increased MAO activity or by increased calpain-1 levels, whereas NOX2, NOX4, and XO may contribute to increased cytosolic ROS generation.

ROS, reactive oxygen species; DC, diabetic cardiomyopathy; FA, fatty acid; TAG, triacylglycerols; AGE, advanced glycation end product; NOX, NADPH oxidases; XO, xanthine oxidase; GLUT, glucose transport protein; CD, cluster of differentiation; FATP, fatty acid transport protein; ACS, acetyl-CoA synthetase; PPARα, peroxisome proliferator-activated receptor α; FAO, fatty acid oxidation; PPP, pentose phosphate pathway; NADPH, nicotinamide adenine dinucleotide phosphate; HBP, hexosamine biosynthetic pathway; O-GlcNAc, O-linked β-N-acetylglucosamine; SERCA, sarco(endo) plasmic reticulum Ca²⁺-ATPase; DAG, diacylglycerols; TAG, triacylglycerols; CPT, carnitine palmitoyltransferase; TCA, trichloroacetic acid; MAO, monoamine oxidases; PDH, pyruvate dehydrogenase; ADP, adenosine diphosphate; ATP, adenosine triphosphate; UCP, uncoupling protein.

Fig. 2. Potential mechanisms and effects of impaired Ca²⁺ handling in DC. Impairment in cardiomyocyte Ca²⁺ influx and efflux, impaired release and reuptake of Ca²⁺ by the SR, and impaired Ca²⁺ uptake by the mitochondria which may subsequently impair ATP regeneration and thereby contribute to systolic and diastolic dysfunction in DC.

DC, diabetic cardiomyopathy; SR, sarcoplasmic reticulum; ATP, adenosine triphosphate; NCX, Na⁺/Ca²⁺ exchanger; LTCC, L-type Ca²⁺ channels; TCA, trichloroacetic acid; DH, dehydrogenase; RyR, ryanodine receptor; CaMKII, calmodulin-dependent protein kinase II; O-GlcNAc, O-linked β-N-acetylglucosamine; SERCA, sarco(endo)plasmic reticulum Ca²⁺-ATPase; AGE, advanced glycation end product.

Fig. 3. Novel mitochondrial mechanisms potentially contributing to DC. Decreased SIRT3 activity in DC may contribute to impaired oxidative ATP regeneration, increased ROS production and suppression of mitophagy. MAO and calpain 1 may contribute to increased mitochondrial ROS. O-GlcNAcylation and acyl-CoA driven posttranslational modification of Drp1 and Opa1 may contribute to mitochondrial fragmentation. Decreased levels of PINK and Parkin may suppress mitophagy in DC. Mitochondrial fragmentation and suppression of mitophagy may further amplify mitochondrial dysfunction in DC.

DC, diabetic cardiomyopathy; SIRT3, sirtuin 3; ATP, adenosine triphosphate; ROS, reactive oxygen species; MAO, monoamine oxidases; O-GlcNAc, O-linked β-N-acetylglucosamine; TCA, trichloroacetic acid.