Abstract 036: Interference With PPARγ in the Endothelium Produces Endothelial Dysfunction in the Cerebral Circulation in Response to Activation of the Endogenous Renin-Angiotensin System

Abstract

Low salt diet (LSD) is beneficial in salt-sensitive hypertension but may provoke cardiovascular risk in patients with heart failure, diabetes, or other cardiovascular abnormalities because of renin-angiotensin system (RAS) activation. PPARγ is a transcription factor which promotes an anti-oxidant pathway in the endothelium. We studied transgenic mice expressing a dominant-negative mutation in PPARγ selectively in the endothelium (E-DN) to test the hypothesis that endothelial PPARγ plays a protective role in response to LSD-mediated RAS activation. Plasma renin and angiotensin were significantly and equally increased in all mice fed LSD for 6-weeks (Renin - NT: 39±7 vs 20±1 ng/ml; E-DN: 34±1 vs 16±4 ng/ml; Ang - NT: 257±54 vs 47±6 pg/ml; E-DN: 294±69 vs 63±14 pg/ml p<0.05, n=5). Vasorelaxation to acetylcholine was not affected in basilar artery from E-DN at baseline, but was significantly and selectively impaired in E-DN after LSD (33±5 vs 69±2%, p<0.05, n=6). Unlike basilar artery, LSD was not sufficient to induce vascular dysfunction in carotid artery (carotid artery: 86±4 vs 92±3%, n=5). Endothelial dysfunction in the basilar artery from E-DN mice fed LSD was attenuated by scavengers of superoxide (improved from 29±5% to 55±7%, n=6), inhibitors of NADPH oxidase (improved from 23±3% to 54±7%, p<0.05, n=6), or blockade of the angiotensin-II AT1 receptor (improved from 31±5% to 64±9%, p<0.05, n=5). Gene expression levels of Nox2 was elevated (2.1±0.3 vs 0.4±0.1, p<0.05, n=7) while those of antioxidant enzymes catalase and SOD3 were blunted in cerebral vessels of E-DN mice on a LSD (catalase: 0.5±0.1 vs 2.5±0.2; SOD3: 0.2±0.1 vs 1.1±0.1, p<0.05, n=7). Simultaneous AT1 and AT2 receptor blockade revealed the restoration of endothelial function after AT1 receptor blockade was not a consequence of AT2 receptor activation (59±10 vs 48±2, p<0.05, n=4). 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, mediated at least in part, through AT1 receptor activation and perturbed redox homeostasis. Moreover, our data suggest that the cerebral circulation may be particularly sensitive to inhibition of PPARγ activity and RAS activation.