Role of Oxidative Stress in Metabolic and Subcellular Abnormalities in Diabetic Cardiomyopathy

Abstract

Although the presence of cardiac dysfunction and cardiomyopathy in chronic diabetes has been recognized, the pathophysiology of diabetes-induced metabolic and subcellular changes as well as the therapeutic approaches for the prevention of diabetic cardiomyopathy are not fully understood. Cardiac dysfunction in chronic diabetes has been shown to be associated with Ca²⁺-handling abnormalities, increase in the availability of intracellular free Ca²⁺ and impaired sensitivity of myofibrils to Ca²⁺. Metabolic derangements, including depressed high-energy phosphate stores due to insulin deficiency or insulin resistance, as well as hormone imbalance and ultrastructural alterations, are also known to occur in the diabetic heart. It is pointed out that the activation of the sympathetic nervous system and renin-angiotensin system generates oxidative stress, which produces defects in subcellular organelles including sarcolemma, sarcoplasmic reticulum and myofibrils. Such subcellular remodeling plays a critical role in the pathogenesis of diabetic cardiomyopathy. In fact, blockade of the effects of neurohormonal systems has been observed to attenuate oxidative stress and occurrence of subcellular remodeling as well as metabolic abnormalities in the diabetic heart. This review is intended to describe some of the subcellular and metabolic changes that result in cardiac dysfunction in chronic diabetes. In addition, the therapeutic values of some pharmacological, metabolic and antioxidant interventions will be discussed. It is proposed that a combination therapy employing some metabolic agents or antioxidants with insulin may constitute an efficacious approach for the prevention of diabetic cardiomyopathy.

Keywords: Ca2+-handling abnormalities; cardiac metabolism; diabetic cardiomyopathy; oxidative stress; renin-angiotensin system; subcellular remodeling; sympathetic nervous system.

Figure 1

Role of oxidative stress in the pathogenesis of diabetic cardiomyopathy.

Figure 2

Role of oxidative stress in subcellular remodeling and Ca²⁺-handling abnormalities in the diabetic heart.

Figure 3

Interventions that may attenuate subcellular remodeling and improve cardiac performance in chronic diabetes.