Heart Research Center of Chonnam National University Hospital, Gwangju 61469, Republic of Korea; Hypertension and Heart Failure, Chonnam National University Hospital, Gwangju 61469, Republic of Korea.
Heart Research Center of Chonnam National University Hospital, Gwangju 61469, Republic of Korea; Hypertension and Heart Failure, Chonnam National University Hospital, Gwangju 61469, Republic of Korea.
Biomed Pharmacother. 2021 Feb;134:111162. doi: 10.1016/j.biopha.2020.111162. Epub 2020 Dec 25.
Non-specific histone deacetylase (HDAC) inhibition reduces high blood pressure in essential hypertensive animal models. However, the exact HDAC isoforms that play a critical role in controlling hypertension are not known. Here, we investigated the role of HDAC5 in vascular contraction, hypertrophy, and oxidative stress in the context of angiotensin II (Ang II)-induced hypertension. Genetic deletion of HDAC5 and treatment with class IIa HDAC inhibitors (TMP269 and TMP195) prevented Ang II-induced increases in blood pressure and arterial wall thickness. Hdac5-knockout mice were also resistant to the thromboxane A2 agonist (U46619)-induced vascular contractile response. Furthermore, the expression of Rho-associated protein kinase (ROCK) 2 was downregulated in the aortas of Ang II-treated Hdac5-knockout mice. Knockdown of HDAC5, RhoA, or ROCK2 reduced collagen gel contraction, whereas silencing of ROCK1 increased it. VSMC hypertrophy reduced on knocking down HDAC5, ROCK1, and ROCK2. Here we showed that genetic deletion of HDAC5 and pharmacological inhibition of class IIa HDACs ameliorated Ang II-induced ROS generation. Moreover, ROCK1 and ROCK2, the downstream targets of HDAC5, influenced ROS generation. The relative protein levels of HDAC5, ROCK1, and ROCK2 were increased both in the cytoplasm and nuclear fraction in response to Ang II stimulation in vascular smooth muscle cells. Inhibition of HDAC5 expression or activity reduced vascular hypertrophy, vasoconstriction, and oxidative stress in the Ang II-induced hypertension model. These findings indicate that HDAC5 may serve as a potential target in the treatment of hypertension.
非特异性组蛋白去乙酰化酶 (HDAC) 抑制可降低原发性高血压动物模型的高血压。然而，控制高血压的确切 HDAC 同工酶尚不清楚。在这里，我们研究了 HDAC5 在血管收缩、肥大和氧化应激中的作用，以及血管紧张素 II (Ang II) 诱导的高血压中的作用。HDAC5 的基因缺失和 IIa 类 HDAC 抑制剂（TMP269 和 TMP195）的治疗可预防 Ang II 引起的血压升高和动脉壁增厚。Hdac5 敲除小鼠也对血栓烷 A2 激动剂 (U46619) 引起的血管收缩反应具有抗性。此外，在 Ang II 处理的 Hdac5 敲除小鼠的主动脉中，Rho 相关蛋白激酶 (ROCK) 2 的表达下调。HDAC5、RhoA 或 ROCK2 的敲低减少了胶原蛋白凝胶的收缩，而 ROCK1 的沉默增加了它。敲低 HDAC5、ROCK1 和 ROCK2 可减少 VSMC 肥大。在这里，我们表明 HDAC5 的基因缺失和 IIa 类 HDAC 的药理学抑制可改善 Ang II 诱导的 ROS 生成。此外，HDAC5 的下游靶点 ROCK1 和 ROCK2 影响 ROS 生成。在血管平滑肌细胞中，Ang II 刺激会导致细胞质和核部分中 HDAC5、ROCK1 和 ROCK2 的相对蛋白水平增加。抑制 HDAC5 的表达或活性可减少 Ang II 诱导的高血压模型中的血管肥大、血管收缩和氧化应激。这些发现表明 HDAC5 可能是治疗高血压的潜在靶点。
