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Interference with PPARγ in the Endothelium Causes Cerebral Vascular Dysfunction in Response to Endogenous Renin‐Angiotensin System Activation
Author(s) -
Nair Anand R,
Agbor Larry N,
Mukohda Masashi,
Hu Chunyan,
Wu Jing,
Sigmund Curt D
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1015.21
Subject(s) - endocrinology , medicine , endothelial dysfunction , renin–angiotensin system , endothelium , basilar artery , receptor , acetylcholine , angiotensin ii , agonist , genetically modified mouse , endogeny , transgene , chemistry , blood pressure , biochemistry , gene
Abnormal activation of the endogenous renin‐angiotensin system (RAS) has been implicated in various cardiovascular (CV) disorders including hypertension, atherosclerosis and stroke. Whereas low salt diet may be beneficial in salt‐sensitive hypertension, it has been proposed to also cause CV risk due to activation of the RAS. The molecular mechanism by which RAS activation mediates vascular dysfunction remains undefined. Peroxisome proliferator‐activated receptor gamma (PPARγ) is a ligand‐activated transcription factor which activates anti‐oxidant and anti‐inflammatory processes and can regulate the actions of angiotensin II (Ang II) in the vasculature. We examined endothelial function in transgenic mice specifically expressing dominant‐negative (DN) mutations in PPARγ in the endothelium (E‐V290M) fed a low salt diet to test the hypothesis that endothelial PPARγ plays a protective role in the vasculature in response to RAS activation. Circulating levels of renin were significantly increased in both non‐transgenic (NT) and E‐V290M mice fed a low‐salt diet for 6 weeks compared to standard chow (NT: 39.3±7.4 vs 19.8±1.3 ng/ml; E‐V290M: 34.3±0.8 vs 16.0±3.8 ng/ml, p<0.05, n=5). Under baseline conditions, vasorelaxation responses to endothelium‐dependent agonist acetylcholine were not affected in E‐V290M mice compared to NT (basilar artery: 66.1±11.8 vs 63.5±3.7%; carotid artery: 93.3±3.6 vs 91.1±4.2%, n=5). Six weeks of low‐salt diet significantly impaired acetylcholine‐mediated vasorelaxation in the basilar artery of E‐V290M mice but not in NT (41.7±7.7 vs 74.2±5.0%, p<0.05, n=5). Unlike basilar artery, 6 weeks of low salt diet was not sufficient to induce vascular dysfunction in carotid artery or aorta of E‐V290M mice (carotid artery: 85.6±4.4 vs 91.9±2.5%, n=5; aorta: 80.8±5.4 vs 87.0±5.6%, n=3). The responses to endothelium‐independent vasodilator sodium nitroprusside (SNP) were not different in E‐V290M mice compared to NT controls. The endothelial dysfunction observed in the basilar artery of E‐V290M mice were attenuated upon ex‐vivo incubation with tempol (improved from 33.1±4.9% to 51.8±8.4% by tempol, n=4). Further, administration of the AT1 receptor blocker, Losartan (0.6g/L drinking water), for the last 2 weeks of low salt diet blunted the endothelial dysfunction observed in the basilar artery of E‐V290M mice (improved from 33.1±4.9% to 64.1±11.0% by Losartan, n=4). We conclude that interference with PPARγ in the endothelium produces endothelial dysfunction in the cerebral circulation in response to low‐salt diet‐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 endogenous RAS. Support or Funding Information NIH and AHA Grants