Contractile apparatus dysfunction early in the pathophysiology of diabetic cardiomyopathy - PubMed (original) (raw)

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Contractile apparatus dysfunction early in the pathophysiology of diabetic cardiomyopathy

Mark T Waddingham et al. World J Diabetes. 2015.

Abstract

Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure in patients. Independent of hypertension and coronary artery disease, diabetes is associated with a specific cardiomyopathy, known as diabetic cardiomyopathy (DCM). Four decades of research in experimental animal models and advances in clinical imaging techniques suggest that DCM is a progressive disease, beginning early after the onset of type 1 and type 2 diabetes, ahead of left ventricular remodeling and overt diastolic dysfunction. Although the molecular pathogenesis of early DCM still remains largely unclear, activation of protein kinase C appears to be central in driving the oxidative stress dependent and independent pathways in the development of contractile dysfunction. Multiple subcellular alterations to the cardiomyocyte are now being highlighted as critical events in the early changes to the rate of force development, relaxation and stability under pathophysiological stresses. These changes include perturbed calcium handling, suppressed activity of aerobic energy producing enzymes, altered transcriptional and posttranslational modification of membrane and sarcomeric cytoskeletal proteins, reduced actin-myosin cross-bridge cycling and dynamics, and changed myofilament calcium sensitivity. In this review, we will present and discuss novel aspects of the molecular pathogenesis of early DCM, with a special focus on the sarcomeric contractile apparatus.

Keywords: Diabetes; Insulin resistance; Myocardium; Prediabetes; Protein kinase C; Rho kinase; Sarcomere.

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Figures

Figure 1

Figure 1

Cellular signaling pathways. A: Cellular signaling pathways driving contractile dysfunction in early diabetic cardiomyopathy; B: Cellular signaling pathways involved in the development of overt LV diastolic dysfunction in diabetes. ANGII: Angiotensin II; DAG: Diacylglycerol; NADPH: Nicotinamide adenine dinucleotide phosphate; PKC: Protein kinase C; RAAS: Renin angiotensin aldosterone system; ROCK: Rho kinase; AGE: Advanced glycation end products; ANG1-7: Angiotensin 1-7; ETC: Electron transport chain; iNOS: Inducible nitric oxide synthase; NF-κB: Nuclear factor-κB; NO: Nitric oxide; SOD: Superoxide dismutase; LV: Left ventricle.

Figure 2

Figure 2

Subcellular alterations in various compartments of the cardiomyocyte in diabetic cardiomyopathy. PLB: Phospholamban; SERCA: Sarcoplasmic reticulum Ca2+-ATPase; SR: Sarcoplasmic reticulum; RyR: Ryanodine receptor.

Figure 3

Figure 3

Illustration of the cardiac sarcomere indicating the location of actin thin-filament and myosin thick-filament accessory proteins involved in the regulation of actin-myosin cross-bridge dynamics and kinetics. C0-C10: Immunoglobulin-like and fibronectin-like domains of myosin binding protein C; MD: M-domain of myosin binding protein C containing protein kinase phosphorylation sites.

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