Pathophysiological Mechanisms of Cardiovascular Dysfunctions in Insulin Resistance Syndrome

Although insulin resistance is recognized as a potent and prevalent risk factor for coronary heart disease; however, the molecular mechanisms linking insulin resistance with cardiovascular disease remains to be fully identified. Therefore, in this project we plan to investigate the molecular mechanisms linking insulin resistance with cardiovascular disease. Specifically, we will examine the effects of high cholesterol-fructose (HCF) -induced insulin resistance on metabolism, functions, and insulin signaling in cardiovascular system. Our previous findings suggest that HCF-diet-induced insulin resistance not only in metabolic tissues but also in cardiac tissues. In addition, the cardiac contractile function was also attenuated in insulin resistant rat heart. Therefore, in the first year of this project, we plan to investigate whether HCF-diet can induce vascular insulin resistance and attenuated reactivity to vasodilator or vasoconstrictor in vessels. The blood pressure changes in response to a variety of vasoconstrictor and vasodilator stimuli and intravital microscope techniques will be used to evaluate the macrovacular and microvascular functions in age-matched control rats and high cholesterol-fructose (HCF) diet-induced insulin resistance rats. In the second year, we will investigate the molecular mechanisms of HCF-induced cardiac insulin resistance and myocardial contractile dysfunctions. In order to clarify whether the cardiac glucose and fatty acid uptake activities will be attenuated in insulin resistant rats; the steady-state cardiac fatty acid and glucose uptake activities will be measured by euglycemic-hyperinsulinemic clamp methods. Furthermore, we will also clarify whether insulin signaling pathway liking with cardiac metabolism and contractility in age-matched control rats and HCF-induced insulin resistant rats. The activation of insulin signaling pathway and cardiac functional proteins expression will be measured in palmitate-induced insulin resistant cardiac myoblasts (H9C2). In the third year, we will investigate the role of insulin signaling pathway in HCF-induced vascular insulin resistance and vascular dysfunctions. For evaluation of vascular endothelium functions, the plasma NO, eNOS mRNA and protein levels as well as eNOS activities will be measured. The steady-state glucose uptake activities as well as insulin-stimulated glucose and fatty acid transporter translocation to the plasma membrane will be determined in HCF-induced insulin resistant vessels. The insulin signaling pathway linking with vascular metabolism and functions will be also determined in vivo and in vitro. Identifying the molecular mechanisms of insulin resistance on cardiovascular system can lead to a better understanding of the disease pathogenesis and the development of possible interventions against disease. Therefore, any positive outcomes of this project will not only help us understand the pathophysiological mechanisms of insulin resistance and CVD for diabetes, but also shed some light on possible therapeutic interventions at the cellular and molecular levels for attenuation of coronary artery disease in diabetic patients.

Project ID:PC9709-0947
External Project ID:NSC97-2320-B182-022-MY3