Division of Pulmonary and Critical Care, Department of Medicine and Victoria Johnson Center for Lung Research, Virginia Commonwealth University, Richmond, VA 23298, USA.
Am J Respir Crit Care Med. 2011 May 15;183(10):1402-10. doi: 10.1164/rccm.201007-1106OC. Epub 2011 Feb 4.
Inhibitors of histone deacetylases (HDACs) reduce pressure-overload-induced left ventricular hypertrophy and dysfunction, but their effects on right ventricular (RV) adaptation to pressure overload are unknown.
Determine the effect of the broad-spectrum HDAC inhibitors trichostatin A (TSA) and valproic acid (VPA) on RV function and remodeling after pulmonary artery banding (PAB) in rats.
Chronic progressive RV pressure-overload was induced in rats by PAB. After establishment of adaptive RV hypertrophy 4 weeks after surgery, rats were treated for 2 weeks with vehicle, TSA, or VPA. RV function and remodeling were determined using echocardiography, invasive hemodynamic measurements, immunohistochemistry, and molecular analyses after 2 weeks of HDAC inhibition. The effects of TSA were determined on the expression of proangiogenic and prohypertrophic genes in human myocardial fibroblasts and microvascular endothelial cells.
TSA treatment did not prevent the development of RV hypertrophy and was associated with RV dysfunction, capillary rarefaction, fibrosis, and increased rates of myocardial cell death. Similar results were obtained with the structurally unrelated HDAC inhibitor VPA. With TSA treatment, a reduction was found in expression of vascular endothelial growth factor and angiopoietin-1, which proteins are involved in vascular adaptation to pressure-overload. TSA dose-dependently suppressed vascular endothelial growth factor, endothelial nitric oxide synthase, and angiopoietin-1 expression in cultured myocardial endothelial cells, which effects were mimicked by selective gene silencing of several class I and II HDACs.
HDAC inhibition is associated with dysfunction and worsened remodeling of the pressure-overloaded RV. The detrimental effects of HDAC inhibition on the pressure-overloaded RV may come about via antiangiogenic or proapoptotic effects.
组蛋白去乙酰化酶（HDAC）抑制剂可减少压力超负荷引起的左心室肥大和功能障碍，但它们对右心室（RV）适应压力超负荷的影响尚不清楚。
确定广谱 HDAC 抑制剂曲古抑菌素 A（TSA）和丙戊酸（VPA）对大鼠肺动脉结扎（PAB）后 RV 功能和重塑的影响。
通过 PAB 诱导慢性进行性 RV 压力超负荷。手术后 4 周建立适应性 RV 肥大后，用载体、TSA 或 VPA 治疗 2 周。用超声心动图、侵入性血流动力学测量、免疫组织化学和分子分析在 2 周的 HDAC 抑制后确定 RV 功能和重塑。TSA 对人心肌成纤维细胞和微血管内皮细胞中促血管生成和促肥大基因的表达的影响进行了测定。
TSA 治疗不能预防 RV 肥大的发展，并与 RV 功能障碍、毛细血管稀疏、纤维化和心肌细胞死亡率增加有关。与结构上无关的 HDAC 抑制剂 VPA 相似的结果。TSA 治疗时，发现血管内皮生长因子和血管生成素-1的表达减少，这些蛋白参与血管对压力超负荷的适应。TSA 剂量依赖性地抑制培养的心肌内皮细胞中血管内皮生长因子、内皮型一氧化氮合酶和血管生成素-1 的表达，这些作用可通过几种 I 类和 II 类 HDAC 的选择性基因沉默来模拟。
HDAC 抑制与压力超负荷 RV 的功能障碍和重塑恶化有关。HDAC 抑制对压力超负荷 RV 的不良影响可能是通过抗血管生成或促凋亡作用引起的。
