AKAP150-TRPV4 regulation of endothelial function in obesity

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Abstract. More than one-third of U.S. adults suffer from obesity, which is also an underlying risk factor for cardiovascular disorders including hypertension, stroke, and heart disease. It is, therefore, extremely important to understand how obesity promotes the development of these disorders. Obesity-induced endothelial dysfunction plays a crucial role in the development of cardiovascular abnormalities. In this application, we propose to address a major gap in the knowledge about pathological mechanisms for obesity-induced endothelial dysfunction. In resistance-sized arteries, endothelial Ca2+ signaling mechanisms regulate endothelium-dependent vasodilation. However, endothelial Ca2+ signaling mechanisms remain unexplored in obesity. We recently showed that Ca2+ influx through individual TRPV4 (transient receptor potential vanilloid 4) channels promotes endothelium- dependent vasodilation. Moreover, A kinase anchoring protein 150 (AKAP150), which can anchor protein kinase A and protein kinase C, is a key regulator of TRPV4 channel activity in the endothelium. We postulate that obesity-induced endothelial dysfunction reflects an impairment of AKAP150-TRPV4 channel regulation of endothelial function. Our preliminary data demonstrate that TRPV4 channel function and endothelium-dependent vasodilation are impaired, and blood pressure is elevated in high-fat diet-fed obese mice. Interestingly, TRPV4 channel function and TRPV4-mediated vasodilation were restored by peroxynitrite inhibitors, implicating a major role for peroxynitrite in obesity-induced endothelial dysfunction. Peroxynitrite has been previously implicated in vascular disorders, however, the molecular mechanisms for peroxynitrite-induced alteration of endothelial function are not known. Our data support the concept that peroxynitrite targets endothelial AKAP150 to lower TRPV4 channel activity. Therefore, we propose to test the hypothesis that peroxynitrite-induced impairment of AKAP150-TRPV4 regulation of endothelial function contributes to obesity-induced hypertension. In Specific Aim 1, we will test the hypothesis that AKAP150-TRPV4 channel regulation of endothelial Ca2+ signaling is impaired in obesity. We will also determine whether endothelium-specific deletion of AKAP150 or TRPV4 channels elevates resting blood pressure. In Specific Aim 2, we will determine how peroxynitrite impairs AKAP150-TRPV4 regulation of endothelial function, and test the hypothesis that elevated peroxynitrite levels disrupt AKAP150- TRPV4 regulation of endothelial function in obesity. These studies will identify new pathological mechanisms for and novel therapeutic strategies against cardiovascular abnormalities in obesity.