Centre for Pharmacology and Therapeutics, Experimental Medicine, Imperial College London, Du Cane Rd, London W12 ONN, UK.
Circulation. 2012 Jul 24;126(4):455-67. doi: 10.1161/CIRCULATIONAHA.112.103176. Epub 2012 Jun 18.
Epigenetic programming, dynamically regulated by histone acetylation, is a key mechanism regulating cell proliferation and survival. Little is known about the contribution of histone deacetylase (HDAC) activity to the development of pulmonary arterial hypertension, a condition characterized by profound structural remodeling of pulmonary arteries and arterioles.
HDAC1 and HDAC5 protein levels were elevated in lungs from human idiopathic pulmonary arterial hypertension and in lungs and right ventricles from rats exposed to hypoxia. Immunohistochemistry localized increased expression to remodeled vessels in the lung. Both valproic acid, a class I HDAC inhibitor, and suberoylanilide hydroxamic acid (vorinostat), an inhibitor of class I, II, and IV HDACs, mitigated the development of and reduced established hypoxia-induced pulmonary hypertension in the rat. Both valproic acid and suberoylanilide hydroxamic acid inhibited the imprinted highly proliferative phenotype of fibroblasts and R-cells from pulmonary hypertensive bovine vessels and platelet-derived growth factor-stimulated growth of human vascular smooth muscle cells in culture. Exposure to valproic acid and suberoylanilide hydroxamic acid was associated with increased levels of p21 and FOXO3 and reduced expression of survivin. The significantly higher levels of expression of cKIT, monocyte chemoattractant protein-1, interleukin-6, stromal-derived factor-1, platelet-derived growth factor-b, and S100A4 in R-cells were downregulated by valproic acid and suberoylanilide hydroxamic acid treatment.
Increased HDAC activity contributes to the vascular pathology of pulmonary hypertension. The effectiveness of HDAC inhibitors, valproic acid, and suberoylanilide hydroxamic acid, in models of pulmonary arterial hypertension supports a therapeutic strategy based on HDAC inhibition in pulmonary arterial hypertension.
表观遗传编程受组蛋白乙酰化的动态调控，是调节细胞增殖和存活的关键机制。组蛋白去乙酰化酶（HDAC）活性对肺动脉高压的发展的贡献知之甚少，肺动脉高压的特征是肺小动脉和小动脉的结构重塑明显。
在人类特发性肺动脉高压患者的肺组织中和在缺氧暴露的大鼠的肺和右心室中，HDAC1 和 HDAC5 蛋白水平升高。免疫组织化学将表达增加定位于肺中的重塑血管。类 I HDAC 抑制剂丙戊酸和类 I、II 和 IV HDAC 抑制剂 suberoylanilide hydroxamic acid（vorinostat）均减轻了大鼠的肺动脉高压的发展并减少了已建立的缺氧诱导的肺动脉高压。丙戊酸和 suberoylanilide hydroxamic acid 均抑制了来自肺动脉高压牛血管的成纤维细胞和 R 细胞的受印迹的高增殖表型以及血小板衍生生长因子刺激的人血管平滑肌细胞在培养中的生长。丙戊酸和 suberoylanilide hydroxamic acid 的暴露与 p21 和 FOXO3 水平的升高和 survivin 表达的降低相关。丙戊酸和 suberoylanilide hydroxamic acid 处理可下调 R 细胞中 cKIT、单核细胞趋化蛋白-1、白细胞介素-6、基质衍生因子-1、血小板衍生生长因子-b 和 S100A4 的表达水平显著升高。
HDAC 活性的增加导致肺动脉高压的血管病理。HDAC 抑制剂丙戊酸和 suberoylanilide hydroxamic acid 在肺动脉高压模型中的有效性支持基于肺动脉高压中 HDAC 抑制的治疗策略。
