Dysregulated Phosphatidylcholine Metabolism Links to Cardiac Maladaptive Remodeling during Insulin Resistance Progression

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 the 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. In addition, it is largely unknown whether the individual changes in metabolic homeostasis and physiology that are observed in cardiomyopathy/heart failure patients are adaptive or maladaptive, and how these changes related with the disease evolution. Our previous study demonstrated that cardiac structural and functional remodeling was coincided with metabolic profiles alteration (metabolomics) in the insulin resistant animals. The lipid metabolites alteration was further analyzed by OPLS-DA, we found that phosphatidylcholine (PC) metabolites (including PC, arachidonic acid, and lysoPC) were significantly increased in insulin resistant animals. However, the causal relationship and pathogenesis of PC metabolites on cardiac maladaptive remodeling during insulin resistance progression needs further investigation. Herein, in this project, we plan to elucidate how metabolic and cardiovascular systems interplay during the insulin resistance progression and further explore when animal gradually decline its insulin sensitivity how does PC and other potential metabolites be altered dynamically and how do these metabolites promote heart to proceed maladaptive remodeling. To achieve the project goals, three aims are proposed. Specific aim 1, the metabolomics will be performed in animals with differential severity level of insulin resistance to show how the dynamic alteration of PC metabolites and global metabolomic profiles during insulin resistance progression. In addition to PC metabolites, other potential disease markers will also be selected in this aim. Specific aim 2, the differential severity level of insulin resistant animal models will be employed to explore how dysregulation of PC metabolites can influence the cardiac structural, functional, and metabolic remodelings dynamically as well as delineate its underlying mechanisms. Specific aim 3 is to clarify the dynamic interaction and causal relationship between metabolic and cardiovascular systems during insulin resistance progression. Accordingly, the pathogenesis of insulin resistant cardiomyopathy will be explored in this aim. 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:PC10308-1272
External Project ID:MOST103-2320-B182-008