Role of the histone deacetylase inhibitor valproic acid in high-fat diet-induced hypertension via inhibition of HDAC1/angiotensin II axis

BACKGROUND: Obesity is known as an epidemic worldwide because of consumption of westernized high-fat diets and one of the major risk factors of hypertension. Histone deacetylases (HDACs) control gene expression by regulating histone/non-histone protein deacetylation. HDAC inhibitors exert anti-cancer and anti-inflammatory effects and play a protective role in cardiovascular diseases. In the present study, we tested the effect of an FDA-approved pan-HDAC inhibitor valproic acid (VPA) on high-fat diet (HFD)induced hypertension in mice. Furthermore, we examined the mechanism of VPA-induced prevention of hypertension. METHODS: Nine-week-old male C57BL/6 mice were fed either a normal diet (ND) or HFD. When the HFD group reached a prehypertensive phase (130-140 mm Hg systolic blood pressure), VPA was administered for 6 days (300 mg kg(-1) per day). Body weights and blood pressure (BP), expression of renin-angiotensin system (RAS) components and HDAC1 were determined. The direct role of HDAC1 in the expression of RAS components was investigated using gene silencing. RESULTS: HFD accelerated the increase in body weight from 22.4 +/- 1.3 to 31.9 +/- 3.0 compared to in the ND group from 22.7 +/- 0.9 to 26.0 +/- 1.7 (P = 0.0134 ND vs HFD), systolic BP from 118.5 +/- 5.7 to 145.0 +/- 3.0 (P < 0.001), and diastolic BP from 91.0 +/- 13.6 to 121.0 +/- 5.0 (P = 0.006); BP was not altered in the ND group. HFD increased RAS components and HDAC1 in the kidneys as well as leptin in the plasma. VPA administration prevented the progression of hypertension and inhibited the increase in expression of HDAC1 and RAS components. VPA did not affect plasma leptin level. Knockdown of HDAC1 in MDCK cells decreased the expression of angiotensinogen and type 1 angiotensin II receptor. CONCLUSIONS: VPA prevented HFD-induced hypertension by downregulating angiotensin II and its receptor via inhibition of HDAC1, offering a novel therapeutic option for HFD-induced hypertension.