The Role of Secretory Phospholipase A2 and Lysophosphatidylcholine in Maladaptive Remodeling of Insulin Resistant Heart

A close link between cardiomyopathy/heart failure (HF) and diabetes mellitus (DM) has long been recognized in the clinical setting. However, the challenge of understanding the association between DM and cardiomyopathy/HF is complicated by the multifaceted interplay between various hemodynamic, metabolic, and other physiological factors that ultimately impact on cardiovascular system. Recently, several mechanisms have been suggested to explain the increased incidence of cardiomyopathy/HF in diabetic patients, including the hypertrophic influence of insulin, the adverse effects of hyperglycemia, increased oxidative stress, and hyperactivity of neurohumoral systems, such as the renin-angiotensin-aldosterone and adrenergic systems. However, the multifarious web of interconnected processes begins with the onset of DM and the cumulative effects on the cardiac abnormalities may not become clinically apparent for several years or more. Thus, in terms of the actual impact of DM on the cardiomyopathy/HF, we are still only seeing the tip of the proverbial iceberg today. Currently, increasing attention has been paid to insulin resistance as a distinct cause of cardiac dysfunction and HF in diabetic patients. Insulin resistance and abnormal glucose metabolism are very common in HF patients, being identified in 43% of these patients, and such abnormalities are associated with decreased cardiac function. Many evidences have emerged that myocardial insulin resistance is central to altered metabolism in the failing heart and may play a crucial role in the development of cardiomyopathy/HF. Our previous study demonstrated that insulin resistance caused heart to undergo structural, functional, and metabolic remodeling which was coincided with elevation of sPLA2 (secretory phospholipase A2) and lysoPC (lysophosphatidylcholine) levels in high-fructose-induced insulin resistant animals. However, the role of sPLAs and its generated lysoPC in the pathogenesis of cardiac maladaptive remodeling during insulin resistance progression needs further investigation. Herein, in this project, we plan to determine whether alteration of sPLA2 and its generated lysoPC levels accompanies a decline in insulin sensitivity, elucidate whether sPLA2/lysoPC involved maladaptive remodeling in insulin resistant heart, and further explore the molecular mechanisms of sPLA2/lysoPC involves in insulin resistant heart to undergo maladaptive remodeling. To achieve the project goals, three aims are proposed. Specific aim 1, the metabolomics will be performed in animals with differential severity of insulin resistance to show the dynamic alteration of sPLA2/lysoPC levels during gradually decline the insulin sensitivity. Specific aim 2 is to evaluate whether treatment insulin resistant rats with sPLA2 inhibitor (varespladib, A-002) can prevent heart to undergo the maladaptive structural, functional, and metabolic remodeling. Specific aim 3 is to explore the molecular mechanisms of sPLA2/lysoPC involves in maladaptive remodeling of insulin resistant heart. Given the study of maladaptive, pathological remodeling dynamic processes in the heart can provide new information for advancement of our knowledge in the context of insulin resistant cardiomyopathy/HF and will suggest new molecular targets for therapeutic intervention.

Project ID:PC10408-1266
External Project ID:MOST104-2320-B182-015