DJ-1/park7 modulates vasorelaxation and blood pressure via epigenetic modification of endothelial nitric oxide synthase

摘要

AimsDJ-1/park7, a multifunctional protein, may play essential roles in the vascular system. However, the function of DJ-1/park7 in vascular contractility has remained unclear. The present study was designed to investigate whether the DJ-1/park7 is involved in the regulation of vascular contractility and systolic blood pressure (SBP).Methods and resultsNorepinephrine (NE) elevated contraction in endothelium-intact vessels in a dose-dependent manner, to a greater extent in DJ-1/park7 knockout (DJ-1/park7-/-) mice than in wild-type (DJ-1/park7+/+) mice. Acetylcholine inhibited NE-evoked contraction in endothelium-intact vessels, and this was markedly impaired in DJ-1/park7 -/- mice compared with DJ-1/park7+/+. Nitric oxide (NO) production (82.1 ± 2.8% of control) and endothelial NO synthase (eNOS) expression (61.7 ± 8.9%) were lower, but H2O2 production (126.4 ± 8.6%) was higher, in endothelial cells from DJ-1/park7-/- mice than in those from DJ-1/park7+/+ controls; these effects were reversed by DJ-1/park7-overexpressing endothelial cells from DJ-1/park7-/- mice. Histone deacetylase (HDAC)-1 recruitment and H3 histone acetylation at the eNOS promoter were elevated and diminished, respectively, in DJ-1/park7-/- mice compared with DJ-1/park7+/+ controls. Moreover, SBP was significantly elevated in DJ-1/park7-/- mice compared with DJ-1/park7+/+ controls, but this elevation was inhibited in mice treated with valproic acid, an inhibitor of Class I HDACs including HDAC-1.ConclusionThese results demonstrate that DJ-1/park7 protein may be implicated in the regulation of vascular contractility and blood pressure, probably by the impairment of NO production through H2O2-mediated epigenetic inhibition of eNOS expression.