Nitroalkene-Mediated Vascular Protection and Ischemic Stroke

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DESCRIPTION (provided by applicant): Ischemic stroke results from a transient or permanent local reduction of cerebral blood flow, characterized by a set of cellular disturbances. With a mortality rate of 30%, stroke is the third leading causes of death and the leading cause of adult disability in the United States. Unfortunately, development of effective therapies is seriously limited by the rapid development of irreversible brain injury following ischemia. Recently, increasing data suggest that peroxisome proliferator- activated receptor-3 (PPAR3) and angiotensin II (Ang II) type 1 receptor (AT1R) are two critical mediators in the pathogenesis of ischemic brain damage. Nitrated oleic acid (OA-NO2) and linoleic acid (LNO2), nitroalkenes formed in nitric oxide (NO)-dependent oxidative reactions, have been found in human plasma and are thought to regulate physiological functions in multiple cell types. Of significance, we have shown that both OA-NO2 and LNO2 are the endogenous PPAR3 ligands. Also, our preliminary studies have documented for the first time that intracerebroventricular administration of OA-NO2 can reduce cerebral infarct volume and edema in mice after 24h of middle cerebral artery (MCA) occlusion. Moreover, we have found that OA-NO2 can bind to AT1R and inhibit its signaling in vascular smooth muscle cells (VSMCs). Furthermore, we have also found that OA-NO2 can inhibit inflammatory reaction in cerebral VSMCs and cerebral vascular endothelial cells (CECs) after exposure to Oxygen Glucose Deprivation (OGD). These findings suggest that nitroalkenes play a critical protective role in ischemic brain damage. In this proposal, we will test the central hypothesis that nitroalkenes (e.g. OA-NO2) may inhibit cerebral ischemia-induced vascular inflammation to exert neuronal protective effects by inhibition of the AT1R signaling pathway and activation of PPAR3-dependent cascade. Specifically, we will define 1) that OA-NO2 inhibits OGD-induced inflammation in cerebral vascular cells via AT1R and PPAR3 signaling pathways; 2) that vascular- selective activation of PPAR3 contributes to the neuronal protection of OA-NO2 in ischemic stroke; 3) that vascular-selective inhibition of AT1R signaling contributes to the neuronal protection of OA-NO2 in ischemic stroke. It is anticipated that elucidating the mechanism of OA-NO2-mediated brain protection in cerebral ischemia will lead to a better understanding of endogenous signaling actions of nitroalkenes in ischemic stroke and will set strong basis for new perspectives on rational drug design and development of nitroalkene derivatives for the treatment of stroke.