title: 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(-/-)) 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.
authors.affiliation: Cardiovascular Endocrinology Section, Endocrinology, Diabetes, and Hypertension Division (L.H.P., T.M.Y., G.K.A., G.H.W.), and Division of Vascular and Endovascular Surgery (L.A.O., W.T.S., O.M.R., R.A.K.), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Luminita H
authors.initials: LH
authors.lastname: Pojoga
authors.affiliation: Cardiovascular Endocrinology Section, Endocrinology, Diabetes, and Hypertension Division (L.H.P., T.M.Y., G.K.A., G.H.W.), and Division of Vascular and Endovascular Surgery (L.A.O., W.T.S., O.M.R., R.A.K.), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Tham M
authors.initials: TM
authors.lastname: Yao
authors.affiliation: Cardiovascular Endocrinology Section, Endocrinology, Diabetes, and Hypertension Division (L.H.P., T.M.Y., G.K.A., G.H.W.), and Division of Vascular and Endovascular Surgery (L.A.O., W.T.S., O.M.R., R.A.K.), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Opsasnick
authors.affiliation: Cardiovascular Endocrinology Section, Endocrinology, Diabetes, and Hypertension Division (L.H.P., T.M.Y., G.K.A., G.H.W.), and Division of Vascular and Endovascular Surgery (L.A.O., W.T.S., O.M.R., R.A.K.), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Waleed T
authors.initials: WT
authors.lastname: Siddiqui
authors.affiliation: Cardiovascular Endocrinology Section, Endocrinology, Diabetes, and Hypertension Division (L.H.P., T.M.Y., G.K.A., G.H.W.), and Division of Vascular and Endovascular Surgery (L.A.O., W.T.S., O.M.R., R.A.K.), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Ossama M
authors.initials: OM
authors.lastname: Reslan
authors.affiliation: Cardiovascular Endocrinology Section, Endocrinology, Diabetes, and Hypertension Division (L.H.P., T.M.Y., G.K.A., G.H.W.), and Division of Vascular and Endovascular Surgery (L.A.O., W.T.S., O.M.R., R.A.K.), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Gail K
authors.initials: GK
authors.lastname: Adler
authors.affiliation: Cardiovascular Endocrinology Section, Endocrinology, Diabetes, and Hypertension Division (L.H.P., T.M.Y., G.K.A., G.H.W.), and Division of Vascular and Endovascular Surgery (L.A.O., W.T.S., O.M.R., R.A.K.), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Gordon H
authors.initials: GH
authors.lastname: Williams
authors.affiliation: Cardiovascular Endocrinology Section, Endocrinology, Diabetes, and Hypertension Division (L.H.P., T.M.Y., G.K.A., G.H.W.), and Division of Vascular and Endovascular Surgery (L.A.O., W.T.S., O.M.R., R.A.K.), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts raouf_khalil@hms.harvard.edu.
authors.forename: Raouf A
authors.initials: RA
authors.lastname: Khalil
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000293:injuries* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051242:Caveolin 1 / Q000172:deficiency / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D000077545:Eplerenone; D006335:Heart Injuries / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D008958:Models, Molecular; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000172:deficiency*; D009690:Nucleic Acid Conformation; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D051242:Caveolin 1; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D000804:Angiotensin II; D013148:Spironolactone; D009569:Nitric Oxide; D000077545:Eplerenone; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester