Abstract 9389: Histone Deacetylase 4 Causes Vascular Inflammation and Mediates Development of Hypertension in Spontaneous Hypertensive Rats

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Histone deacetylases (HDAC)s are transcription factors which play important roles on structural remodeling of chromatin. It is recently clarified that HDAC4 mediates heart failure and vascular smooth muscle cells (SMCs) hypertrophy. Moreover our recent study demonstrated that HDAC4 protein increases in mesenteric artery from spontaneous hypertensive rats (SHR) compared with Wistar Kyoto rats (WKY). Vascular inflammation is essential for pathogenesis of hypertension. We therefore examined whether HDAC4 affects on vascular inflammatory responses and mediates hypertensive vascular diseases. Protein expression (n=6-7, P<0.01) and activity (n=3-5, P<0.01) of HDAC4 in rat mesenteric arterial SMCs were increased by TNF-α (10 ng/ml, 1-3 h). An HDACs inhibitor, trichostatin A (TSA) (10 μM, pretreatment for 30 min), inhibited TNF (10 ng/ml, 24 h)-induced vascular cell adhesion molecule (VCAM)-1 expression (n=4, P<0.01). TSA also inhibited TNF (20 min)-induced phosphorylation of NF-κB (n=4, P<0.01). HDAC4 siRNA inhibited TNF-induced VCAM-1 (n=3-6, P<0.01), monocyte adhesion (n=6, P<0.05), phosphorylation (n=3-6, P<0.05) and transcriptional activity (n=4-5, P<0.05) of NF-κB. Furthermore, HDAC4 siRNA inhibited TNF-induced reactive oxygen species (ROS) production (n=4, P<0.01). In vivo study, blood pressure (n=4, P<0.05), ROS production (n=2) and VCAM-1 expression (n=4) in isolated mesenteric artery were increased in SHR compared with WKY, which were prevented by a long-term TSA treatment to SHR (100, 500 μg/kg/day, 3 weeks). In isolated mesenteric artery, the increased angiotensin II-induced contraction in SHR was reversed by a TSA treatment (n=4-6, P<0.01). The endothelium-dependent relaxation induced by acetylcholine in SHR was augmented by TSA (n=6-8, P<0.01). The present results indicate that in vascular SMCs TNF-induced HDAC4 mediates vascular inflammation via VCAM-1 induction through ROS-dependent NF-κB activation. It is also suggested that pro-inflammatory effects as well as hypercontractile effects of HDAC4 may mediate the development of hypertension in SHR. Our results may imply that HDAC4 is a promising important target for drug therapy against essential hypertension.