Contractile apparatus dysfunction early in the pathophysiology of diabetic cardiomyopathy

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.

Clinical Update: Cardiovascular Disease in Diabetes Mellitus

“…In the normal state, excitation-contraction coupling of cardiomyocytes is mediated by several intracellular calcium transporters, including the ryanodine receptor, and relaxation occurs via the ejection of calcium from the cell through the sarcoplasmic reticulum calcium pump 2a (SERCA2a), the sodium-calcium exchanger, and the plasma membrane calcium ATPase. 459 Animal models of diabetes have altered expression, activity, and function of all of these transporters. 458 Reduced SERCA2a activity and consequent calcium overload in the cytosol can cause impaired relaxation as well as altered calcium sensitivity of proteins involved in regulation of the cardiac actomysin system and shifting of cardiac myosin heavy chain isoforms from V1 to V3, which can lead to reduced contractile force.…”

“…458 Reduced SERCA2a activity and consequent calcium overload in the cytosol can cause impaired relaxation as well as altered calcium sensitivity of proteins involved in regulation of the cardiac actomysin system and shifting of cardiac myosin heavy chain isoforms from V1 to V3, which can lead to reduced contractile force. 456,459 …”

Molecular mechanism of lipid-induced cardiac insulin resistance and contractile dysfunction

“…Several other contractile derangements could contribute to contractile dysfunction in the insulin resistant heart, such as changes in accessory proteins of the thick filament, in the actin thin filament or in the extra-sarcomeric cytoskeleton, but some of these changes are still controversial and need further investigation [84]. Taken together, the exact mechanism how cardiac insulin resistance causes contractile dysfunction is not known yet.…”

“…Both rodent models and clinical studies support that lipid-induced insulin resistance eventually precipitates into cardiac contractile dysfunction [84]. Also in vitro, in cardiomyocyte cultures exposed to excess fatty acids, the onset of insulin resistance occurred in association with a marked decrease in contractile activity of the cardiomyocytes [32].…”

“…It is generally accepted that reduced myofibrillar ATPase activity is associated with contractile dysfunction during the onset of insulin resistance [84]. The underlying mechanism for decreased activity of this ATPase is a switch in myosin isozyme expression, i.e., from myosin heavy chain (MHC)-α/α homodimer to the β/β homodimer [92,93].…”