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Pojoga L.H.,Cardiovascular Endocrine Section | Yao T.M.,Cardiovascular Endocrine Section | Opsasnick L.A.,Harvard University | Garza A.E.,Cardiovascular Endocrine Section | And 4 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2014

Hyperglycemia and endothelial dysfunction are associated with hypertension, but the specific causality and genetic underpinning are unclear. Caveolin-1 (cav-1) is a plasmalemmal anchoring protein and modulator of vascular function and glucose homeostasis. Cav- 1 gene variants are associated with reduced insulin sensitivity in hypertensive individuals, and cav-1-/- mice show endothelial dysfunction, hyperglycemia, and increased blood pressure (BP). On the other hand, insulin-sensitizing therapy with metformin may inadequately control hyperglycemia while affecting the vascular outcome in certain patients with diabetes. To test whether the pressor and vascular changes in cav-1 deficiency states are related to hyperglycemia and to assess the vascular mechanisms of metformin under these conditions, wild-type (WT) and cav-1 -/- mice were treated with either placebo or metformin (400 mg/kg daily for 21 days). BP and fasting blood glucose were in cav-1-/-. WT and did not change with metformin. Phenylephrine (Phe)- and KCl-induced aortic contraction was in cav-1-/- , WT; endothelium removal, the nitric-oxide synthase (NOS) blocker L-NAME (Nv-nitro-L-arginine methyl ester), or soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ) enhanced Phe contraction, and metformin blunted this effect. Acetylcholine-induced relaxation was in cav-1-/- . WT, abolished by endothelium removal, L-NAME or ODQ, and reduced with metformin. Nitric oxide donor sodium nitroprusside was more potent in inducing relaxation in cav-1-/- than in WT, and metformin reversed this effect. Aortic eNOS, AMPK, and sGC were in cav-1-/- . WT, and metformin decreased total and phosphorylated eNOS and AMPK in cav-1-/-. Thus, metformin inhibits both vascular contraction and NO-cGMP-dependent relaxation but does not affect BP or blood glucose in cav-1-/- mice, suggesting dissociation of hyperglycemia from altered vascular function in cav-1-deficiency states. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Pojoga L.H.,Cardiovascular Endocrine Section | Adamova Z.,Harvard University | Kumar A.,Harvard University | Stennett A.K.,Harvard University | And 4 more authors.
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2010

Endothelial caveolin-1 (cav-1) is an anchoring protein in plasma membrane caveolae where it binds endothelial nitric oxide synthase (eNOS) and limits its activation, particularly in animals fed a high salt (HS) diet. Cav-1 also interacts with steroid receptors such as the mineralocorticoid receptor (MR). To test the hypothesis that vascular reactivity is influenced by an interplay between MR and cav-1 during HS diet, we examined the effects of MR blockade on NOS-mediated vascular relaxation in normal and cav-1-deficient mice. Wild-type (WT) and cav-1 knockout mice (cav-1-/-) were fed for 14 days a HS (4% NaCl) diet with and without the MR antagonist eplerenone (Epl; 100 mg·kg-1·day-1). After systolic blood pressure (BP) was measured, the thoracic aorta was isolated for measurement of vascular reactivity, and the aorta and heart were used for measurement of eNOS and MR expression. BP was not different between WT + Epl and WT, but was higher in cav-1-/- + Epl than in cav-1-/- mice. Phenylephrine (Phe)-induced vascular contraction was less in cav-1-/- than WT, and significantly enhanced in cav-1-/- + Epl than in cav-1-/-, but not in WT + Epl compared with WT. Endothelium removal and NOS blockade by Nω-nitro-L-arginine methyl ester (L-NAME) enhanced Phe contraction in cav-1-/-, but not cav-1-/- + Epl. ACh-induced aortic relaxation was reduced in cav-1-/- + Epl versus cav-1-/-, but not in WT, Epl compared with WT. Endothelium removal, L-NAME, and the guanylate cyclase inhibitor ODQ abolished the large ACh-induced relaxation in cav-1-/- and the remaining relaxation in the cav-1 -/- + Epl but had similar inhibitory effect in WT and WT + Epl. Real-time RT-PCR indicated decreased eNOS mRNA expression in the aorta and heart, and Western blots revealed decreased total eNOS in the heart of cav-1-/- + Epl compared with cav-1-/-. Vascular and cardiac MR expression was less in cav-1-/- than WT, but not in cav-1-/- + Epl compared with cav-1-/-. Plasma aldosterone (Aldo) was not different between WT and cav-1-/- mice nontreated or treated with Epl. Thus in cav-1 deficiency states and HS diet MR blockade is associated with increased BP, enhanced vasoconstriction, and decreased NOS-mediated vascular relaxation and eNOS expression. The data suggest that, in the absence of cav-1, MR activation plays a beneficial role in regulating eNOS expression/activity and, consequently, the vascular function during HS diet. Copyright © 2010 the American Physiological Society.

Pojoga L.H.,Cardiovascular Endocrine Section | Williams J.S.,Cardiovascular Endocrine Section | Yao T.M.,Cardiovascular Endocrine Section | Kumar A.,Harvard University | And 7 more authors.
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2011

Histone methylation, a determinant of chromatin structure and gene transcription, was thought to be irreversible, but recent evidence suggests that lysine-specific demeth-ylase-1 (LSD1, Kdm1a) induces demethylation of histone H3 lysine 4 (H3K4) or H3K9 and thereby alters gene transcription. We previously demonstrated a human LSD1 phenotype associated with salt-sensitive hypertension. To test the hypothesis that LSD1 plays a role in the regulation of blood pressure (BP) via vascular mechanisms and gene transcription, we measured BP and examined vascular function and endothelial nitric oxide (NO) synthase (eNOS) expression in thoracic aorta of male wild-type (WT) and heterozygous LSD1 knockout mice (LSD1 +/~) fed either a liberal salt (HS; 4% NaCl) or restricted salt diet (LS; 0.08% NaCl). BP was higher in LSD1 +/~ than WT mice on the HS diet but not different between LSD1 +/~ and WT mice on the LS diet. Further examination of the mechanisms of this salt-sensitive hypertension in LSD1 +/~ mice on the HS diet demonstrated that plasma renin activity and plasma levels and urinary excretion of aldosterone were less in LSD1 +/~ than WT, suggesting suppressed renin-angiotensin-aldosterone system. In contrast, phenylephrine (Phe)-induced aortic contraction was greater in LSD1 +/~ than WT mice on the HS diet. Treatment of aortic rings with 1H-[1,2,4]oxadia-zolo[4,3-a]quinoxalin-1-one (ODQ; a blocker of guanylate cyclase) enhanced Phe contraction in LSD1 +/~ compared with WT mice on the HS diet. Acetylcholine (Ach)-induced relaxation was less in LSD1 +/~ than WT mice on the HS diet. Endothelium removal or pretreatment with N^-nitro-L-arginine methyl ester (blocker of NOS) or ODQ abolished Ach-induced relaxation in aorta of WT but had minimal effect in LSD1 +/~. Vascular relaxation to sodium nitroprus-side, an exogenous NO donor and guanylate cyclase activator, was decreased in LSD1 +/~ vs. WT mice on the HS diet. RT-PCR and Western blots revealed decreased eNOS mRNA expression and eNOS and guanylate cyclase protein in the heart and aorta of LSD1 +/~ compared with WT mice on HS diet. Thus, during the HS diet, LSD1 deficiency is associated with hypertension, enhanced vascular contraction, and reduced relaxation via NO-cGMP pathway. The data support a role for LSD1-mediated histone demethylation in the regulation of NOS/guanylate cyclase gene expression, vascular function, and BP during the HS diet. © 2011 the American Physiological Society.

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