(Verbatim from the application): Insulin resistance is associated with an increased risk of hypertension and cardiovascular disease. Data from the applicant's laboratory suggests that endothelial dysfunction may be the mechanism that links insulin resistance to vascular disease. Previous studies demonstrate impaired endothelium dependent vasodilation in small coronary arteries from insulin resistant rats. Moreover, this dysfunction appears to be secondary to a defect in endothelium derived hyperpolarizing factor (EDHF). These data support the existence of a unique situation where the EDHF dilator component is selectively impaired and provides us a model to assess mechanisms leading to impaired EDHF function. Moreover, it also provides us a model to assess compensatory responses of other endothelium derived relaxing factors (NO, prostacyclin) to an EDHF deficit. The overall hypothesis to be examined is that impairment of endothelium-dependent dilator capacity occurs in coronary arteries during JR. Specific hypotheses to be tested are (1) Endothelial dysfunction associated with JR is due to a decreased production of EDHF. (2) Decreased substrate availability and/or abnormally low levels of CYP isoforms account for decreased EDHF production. (3) Endothelial dysfunction associated with JR is due to decreased sensitivity of potassium channels on vascular smooth muscle to EDHF. (4) The NO and prostacyclin systems do not compensate for this loss of dilator capacity. (5) Enhanced PKC activation links IR to vascular dysfunction. To test these hypotheses the following specific aim will be addressed.
Specific aim. Determination of the mechanism of impaired endothelium-dependent vasodilation in insulin resistance. First, we will investigate the effect of JR on dilator responses to exogenous arachidonic acid. Second, we will explore the effect of IRon synthesis of bioactive metabolites of arachidonic acid. Third, we will examine the relationship between endothelial function and levels of CYP and NO synthase (NOS) protein. Fourth, we will determine the effect of application of exogenous arachidonic acid metabolites (epoxyeicosatrienoic acids) and direct activators of the calcium dependent potassium channel on vascular tone. Fifth, we will determine the effect of PKC inhibition on endothelium and vascular smooth muscle dependent vasodilation. Sixth, we will assess the effect of PKC activation on endothelium and vascular smooth muscle dependent vasodilation. And seventh, we will assess the effect of JR on PKC protein expression in small coronary arteries. These data will determine specific mechanisms of endothelial dysfunction in insulin resistance. In addition, the specific role of EDHF and the possible mechanisms for its dysfunction will be determined. Finally, these data will determine the role of PKC in vascular dysfunction associated with IR, which may help to define the global mechanisms linking insulin resistance to vascular disease, This project employs a unique approach, incorporating physiologic, cellular, and molecular biology techniques to address the proposed questions. Findings from this project may provide important information that can be used in future studies to design treatments to prevent or abort the cardiovascular complications of insulin resistance.
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