Estradiol-induced expression of Na⁺-K⁺-ATPase catalytic isoforms in rat arteries: gender differences in activity mediated by nitric oxide donors

Abstract

We tested the hypothesis that previously demonstrated gender differences in ACh-induced vascular relaxation could involve diverse Na+-K+-ATPase functions. We determined Na+-K+-ATPase by measuring arterial ouabain-sensitive 86Rb uptake in response to ACh. We found a significant increase of Na+ pump activity only in aortic rings from female rats (control 206 ± 11 vs. 367 ± 29 nmol 86Rb/K·min–1·g wt tissue–1; P < 0.01). Ovariectomy eliminated sex differences in Na+-K+-ATPase function, and chronic in vivo hormone replacement with 17β-estradiol restored the ACh effect on Na+-K+-ATPase. Because ACh acts by enhancing production of NO, we examined whether the NO donor sodium nitroprusside (SNP) mimics the action of ACh on Na+-K+-ATPase activity. SNP increased ouabain-sensitive 86Rb uptake in denuded female arteries (control 123 ± 7 vs. 197 ± 12 nmol 86Rb/K·min–1·g wt tissue–1; P < 0.05). Methylene blue (an inhibitor of guanylate cyclase) and KT-5823 (a cGMP-dependent kinase inhibitor) blocked the stimulatory action of SNP. Exposure of female thoracic aorta to the Na+/K+ pump inhibitor ouabain significantly decreased SNP-induced and ACh-mediated relaxation of aortic rings. At the molecular level, Western blot analysis of arterial tissue revealed significant gender differences in the relative abundance of catalytic isoforms of Na+-K+-ATPase. Female-derived aortas exhibited a greater proportion of α2-isoform (44%) compared with male-derived aortas. Furthermore, estradiol upregulated the expression of α2 mRNA in male arterial explants. Our results demonstrate that enhancement of ACh-induced relaxation observed in female rats may be in part explained by 1) NO-dependent increased Na+-K+-ATPase activity in female vascular tissue and 2) greater abundance of Na+-K+-ATPase α2-isoform in females.

Effects of obesity and estradiol on Na+/K+-ATPase and their relevance to cardiovascular diseases

“…One of the cardioprotective mechanisms proposed for estradiol involves its ability to increase the activity and expression of Na C /K C -ATPase in vitro (Dzurba et al 1997, Isenovic et al 2002, Sudar et al 2008. Numerous studies, including ours, have shown that estradiol is one of the major regulators of Na C /K C -ATPase in the CV system (Dzurba et al 1997, Isenovic et al 2002, Palacios et al 2004). This explanation is also supported by the observation that estradiol-induced increase in Na C /K C -ATPase a2 expression leads to a significantly higher activity of Na C /K C -ATPase (Palacios et al 2004).…”

“…Numerous studies, including ours, have shown that estradiol is one of the major regulators of Na C /K C -ATPase in the CV system (Dzurba et al 1997, Isenovic et al 2002, Palacios et al 2004). This explanation is also supported by the observation that estradiol-induced increase in Na C /K C -ATPase a2 expression leads to a significantly higher activity of Na C /K C -ATPase (Palacios et al 2004). However, the mechanisms by which estradiol affects Na C /K C -ATPase remain unclear, in both normal and pathological conditions (such as obesity).…”

“…This finding is also supported by the observation that estradiol-induced increase in Na C /K C -ATPase a2 expression leads to a significantly higher Na C /K C -ATPase activity (Palacios et al 2004). Estradiol has also been reported to enhance Na C /K C -ATPase activity in H9C2 cardiac myocytes and rat hearts (Liu et al 2007(Liu et al , 2012.…”

“…Several studies have shown that estradiol is one of the primary Na C /K C -ATPase regulators in the CV system (Dzurba et al 1997, Isenovic et al 2002, Palacios et al 2004). This finding is also supported by the observation that estradiol-induced increase in Na C /K C -ATPase a2 expression leads to a significantly higher Na C /K C -ATPase activity (Palacios et al 2004).…”

High-Salt Diet Inhibits Expression of Angiotensin Type 2 Receptor in Resistance Arteries

“…Mesenteric artery explants were prepared as described 29 and incubated for 24 hours with aldosterone (10 Ϫ12 to 10 Ϫ9 mol/L) or vehicle (control). Thereafter, RNA was extracted and used for reversetranscription PCR experiments.…”