NFAT Regulation of Cystathionine Gamma Lyase Expression in Endothelial Cells is Impaired in Rats Exposed to Intermittent Hypoxia.

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NFAT Regulation of Cystathionine Gamma Lyase Expression in Endothelial Cells is Impaired in Rats Exposed to Intermittent Hypoxia.

Am J Physiol Heart Circ Physiol. 2017 Jan 27;:ajpheart.00952.2015

Authors: Gonzalez Bosc LV, Osmond JM, Giermakowska W, Pace CE, Riggs JL, Jackson-Weaver O, Kanagy NL

Abstract
Sleep apnea is a risk factor for cardiovascular disease, and intermittent hypoxia (IH, 20 episodes/hr of 5% O2/5% CO2 for 7 hr/day) to mimic sleep apnea increases blood pressure and impairs H2S-induced vasodilation in rats. The enzyme that produces H2S, cystathionine gamma lyase (CSE), is decreased in rat mesenteric artery endothelial cells (EC) following in vivo IH exposure. In silico analysis identified putative NFAT binding sites in the CSE promoter. Therefore, we hypothesized that IH exposure reduces [Ca(2+)] activation of calcineurin/NFAT to lower CSE expression and impairs vasodilation. In cultured rat aortic EC, inhibiting calcineurin with cyclosporine A reduced CSE mRNA, CSE protein and luciferase activity driven by a full-length but not a truncated CSE promoter. In male rats exposed to sham or IH conditions for 2 weeks, [Ca(2+)] in EC in small mesenteric arteries from IH rats was lower than in EC from sham rat arteries (Δ fura2 F340/F380 from Ca(2+)-free: IH = 0.05±0.02, Sham = 0.17±0.03, p<0.05) and fewer EC were NFATc3 nuclear-positive in IH rat arteries than in sham rat arteries (IH = 13±3, sham = 59±11%, P<0.05). H2S production was also lower in mesenteric tissue from IH rats vs. sham rats. Endothelium-dependent vasodilation to acetylcholine (ACh) was lower in mesenteric arteries from IH rats than in arteries from sham rats, and inhibiting CSE with beta-cyanoalanine diminished ACh-induced vasodilation in arteries from sham but not IH rats but did not affect dilation to the H2S donor, NaHS. Thus, IH lowers EC [Ca(2+)], NFAT activity, CSE expression and activity, and H2S production while inhibiting NFAT activation lowers CSE expression. The observations that IH exposure decreases NFATc3 activation and CSE-dependent vasodilation support a role for NFAT in regulating endothelial H2S production.

PMID: 28130342 [PubMed - as supplied by publisher]

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