PT  - JOURNAL ARTICLE
AU  - Luminita H. Pojoga
AU  - Tham M. Yao
AU  - Lauren A. Opsasnick
AU  - Waleed T. Siddiqui
AU  - Ossama M. Reslan
AU  - Gail K. Adler
AU  - Gordon H. Williams
AU  - Raouf A. Khalil
TI  - Cooperative Role of Mineralocorticoid Receptor and Caveolin-1 in Regulating the Vascular Response to Low Nitric Oxide–High Angiotensin II–Induced Cardiovascular Injury
AID  - 10.1124/jpet.115.226043
DP  - 2015 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 32--47
VI  - 355
IP  - 1
4099  - http://jpet.aspetjournals.org/content/355/1/32.short
4100  - http://jpet.aspetjournals.org/content/355/1/32.full
SO  - J Pharmacol Exp Ther2015 Oct 01; 355
AB  - Aldosterone interacts with mineralocorticoid receptor (MR) to stimulate sodium reabsorption in renal tubules and may also affect the vasculature. Caveolin-1 (cav-1), an anchoring protein in plasmalemmal caveolae, binds steroid receptors and also endothelial nitric oxide synthase, thus limiting its translocation and activation. To test for potential MR/cav-1 interaction in the vasculature, we investigated if MR blockade in cav-1–replete or –deficient states would alter vascular function in a mouse model of low nitric oxide (NO)–high angiotensin II (AngII)–induced cardiovascular injury. Wild-type (WT) and cav-1 knockout mice (cav-1−/−) consuming a high salt diet (4% NaCl) received Nω-nitro-l-arginine methyl ester (L-NAME) (0.1–0.2 mg/ml in drinking water at days 1–11) plus AngII (0.7–2.8 mg/kg per day via an osmotic minipump at days 8–11) ± MR antagonist eplerenone (EPL) 100 mg/kg per day in food. In both genotypes, blood pressure increased with L-NAME + AngII. EPL minimally changed blood pressure, although its dose was sufficient to block MR and reverse cardiac expression of the injury markers cluster of differentiation 68 and plasminogen activator inhibitor-1 in L-NAME+AngII treated mice. In aortic rings, phenylephrine and KCl contraction was enhanced with EPL in L-NAME+AngII treated WT mice, but not cav-1−/− mice. AngII-induced contraction was not different, and angiotensin type 1 receptor expression was reduced in L-NAME + AngII treated WT and cav-1−/− mice. In WT mice, acetylcholine-induced relaxation was enhanced with L-NAME + AngII treatment and reversed with EPL. Acetylcholine relaxation in cav-1−/− mice was greater than in WT mice, not modified by L-NAME + AngII or EPL, and blocked by ex vivo L-NAME, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), or endothelium removal, suggesting the role of NO-cGMP. Cardiac endothelial NO synthase was increased in cav-1−/− versus WT mice, further increased with L-NAME + AngII, and not affected by EPL. Vascular relaxation to the NO donor sodium nitroprusside was increased with L-NAME + AngII in WT mice but not in cav-1−/− mice. Plasma aldosterone levels increased and cardiac MR expression decreased in L-NAME + AngII treated WT and cav-1−/− mice and did not change with EPL. Thus, during L-NAME + AngII induced hypertension, MR blockade increases contraction and alters vascular relaxation via NO-cGMP, and these changes are absent in cav-1 deficiency states. The data suggest a cooperative role of MR and cav-1 in regulating vascular contraction and NO-cGMP–mediated relaxation during low NO–high AngII–dependent cardiovascular injury.