Abstract 140: Endogenous Renin-angiotensin System Activation Causes Accelerated Cerebral Vascular Dysfunction in Mice Expressing Dominant-negative Mutations in PPARγ in Endothelium

Abstract

Abnormal activation of the renin-angiotensin system (RAS) has been implicated in cardiovascular (CV) disease. Whereas low salt diet (LSD) may be beneficial in salt-sensitive hypertension, it has been proposed to induce CV risk due to RAS activation. Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor which regulates the actions of angiotensin II (ANG) in the vasculature and promotes anti-oxidant pathways. We hypothesize that endothelial PPARγ plays a protective role in the vasculature in response to RAS activation. Transgenic mice specifically expressing dominant-negative (DN) mutations in PPARγ in the endothelium (E-DN) were fed a LSD and endothelial function was measured. Plasma renin and ANG were significantly increased in both non-transgenic (NT) and E-DN mice fed a LSD for 6 weeks compared with normal chow (Renin - NT: 39±7 vs 20±1 ng/ml; E-DN: 34±1 vs 16±4 ng/ml; AngII - NT: 257±54 vs 47±6 pg/ml; E-DN: 294±69 vs 63±14 pg/ml p<0.05, n=5). At baseline, vasorelaxation to acetylcholine (ACh) was not affected in E-DN compared to NT (basilar artery: 66±12 vs 64±4%; carotid artery: 93±4 vs 91±4%, n=5). Six weeks of LSD significantly impaired ACh-mediated relaxation in basilar artery of E-DN but not in NT (42±8 vs 74±5%, p<0.05, n=5). Unlike basilar artery, 6 weeks of LSD was not sufficient to induce vascular dysfunction in carotid artery of E-DN (carotid artery: 86±4 vs 92±3%, n=5). The endothelial dysfunction observed in the basilar artery of E-DN was attenuated upon in vitro incubation with tempol (improved from 29±5% to 55±7%, n=6). Further, administration of the AT1 receptor blocker, Losartan (0.6g/L drinking water) for the last 2 weeks of LSD blunted the endothelial dysfunction observed in the basilar artery of E-DN (improved from 24±2% to 64±9%, n=5). We conclude that interference with PPARγ in the endothelium produces endothelial dysfunction in the cerebral circulation in response to LSD-mediated activation of the endogenous RAS and this dysfunction is mediated, at least in part, through AT1 receptor activation and ROS signaling pathways. Moreover, our data suggest that the basilar artery and perhaps cerebral circulation is particularly sensitive to inhibition of PPARγ activity and activation of the RAS.