Cooperative Role of Mineralocorticoid Receptor and Caveolin-1 in Regulating the Vascular Response to Low Nitric Oxide–High Angiotensin II–Induced Cardiovascular Injury

Abstract

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 2 /2 ) consuming a high salt diet (4% NaCl) received N v -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) 6 MR antagonist eplerenone (EPL) 100 mg/kg per day in food. In both genotypes, blood pressure increased with L-NAME 1 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-NAME1AngII treated mice. In aortic rings, phenylephrine and KCl contraction was enhanced with EPL in L-NAME1AngII treated WT mice, but not cav-1 2/2 mice.AngII-induced contraction was not different, and angiotensin type 1 receptor expression was reduced in L-NAME 1 AngII treated WT and cav-1 2/2 mice. In WT mice, acetylcholine-induced relaxation was enhanced with L-NAME 1 AngII treatment and reversed with EPL. Acetylcholine relaxation in cav-1 2/2 mice was greater than in WT mice, not modified by L-NAME 1 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 2/2 versus WT mice, further increased with L-NAME 1 AngII, and not affected by EPL. Vascular relaxation to the NO donor sodium nitroprusside was increased with L-NAME 1 AngII in WT mice but not in cav-1 2/2 mice. Plasma aldosterone levels increased and cardiac MR expression decreased in L-NAME 1 AngII treated WT and cav-1 2/2 mice and did not change with EPL. Thus, during L-NAME 1 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.

The role of spironolactone on myocardial oxidative stress in rat model of streptozotocin‐induced diabetes

“…Reported effects of aldosterone antagonists on cardiac tissue and circulating aldosterone levels are conflicting. Eplerenone use increased aldosterone levels in hypertensive diastolic failing rat hearts but had no effect on plasma levels in a mouse model of angiotensin‐II infusion . In contrast, spironolactone use increased plasma aldosterone levels in patients with congestive HF .…”

Caveolin-1 Deletion Prevents Hypertensive Vascular Remodeling Induced by Angiotensin II

“…These data are consistent with past reports infusing L-NAME 31 or AngII plus L-NAME 30 in Cav1−/− mice. However, enhanced blood pressure responses have been reported with L-NAME plus AngII infusion 32 and high fat diet 33 in Cav1−/− mice whereas reduced blood pressure response has been reported with AngII infusion in Cav1+/− mice 34 . In the present study, enhanced diastolic blood pressure was also observed in Cav1−/− mice in response to AngII infusion, which may involve the role of Cav1 in promoting AngII desensitization in arterial contraction 33 .…”

New roles of aldosterone and mineralocorticoid receptors in cardiovascular disease: translational and sex-specific effects

“…4). We cannot exclude that an interplay between EC-MRs and caveolin-1 prevents an increase in NO in male subjects, as in the absence of caveolin-1 MR activation upregulates eNOS expression and activity (84,85). However, in obese male subjects, rather than endothelial MR signaling, sympathetic activation appears to be the driver of cardiovascular damage as endothelial dysfunction is attenuated by the treatment with ␤-blockers (29,95).…”