Kim Gwi Ran, Cho Soo-Na, Kim Hyung-Seok, Yu Seon Young, Choi Sin Young, Ryu Yuhee, Lin Ming Quan, Jin Li, Kee Hae Jin, Jeong Myung Ho
aHeart Research Center of Chonnam National University Hospital bDepartment of Forensic Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea cJilin Hospital Affiliated with Jilin University, Jilin, China *Gwi Ran Kim, Soo-Na Cho, and Hyung-Seok Kim contributed equally to the writing of this article.
J Hypertens. 2016 Nov;34(11):2206-19. doi: 10.1097/HJH.0000000000001081.
Histone deacetylase (HDAC) inhibitors have been reported to improve essential and secondary hypertension. However, the specific HDAC that might serve as a therapeutic target and the associated upstream and downstream molecules involved in regulating hypertension remain unknown. Our study was aimed at investigating whether a selective inhibitor of class II HDAC (MC1568) modulates hypertension, elucidating the underlying mechanism.
Hypertension was established by administering angiotensin II (Ang II) to mice before treatment with MC1568. SBP was measured.
Treatment with MC1568 reduced elevated SBP; attenuated arterial remodeling in the kidney's small arteries and thoracic aorta; and inhibited cell cycle regulatory gene expression, vascular smooth muscle cell (VSMC) proliferation, DNA synthesis, and VSMC hypertrophy in vivo and in vitro. Ang II enhanced the expression of phosphorylated HDAC4 and GATA-binding factor 6 (GATA6) proteins, which were specifically localized in the cytoplasm of cells in the arteries of kidneys and in aortas. Forced expression and knockdown of HDAC4 increased and decreased, respectively, the proliferation and expression of cell cycle genes in VSMCs. GATA6, a newly described binding partner of HDAC4, markedly enhanced the size and number of VSMCs. Calcium/calmodulin-dependent kinase IIα (CaMKIIα), but not HDAC4, translocated from the nucleus to the cytoplasm in response to Ang II. CaMKIIα and protein kinase D1 were associated with VSMC hypertrophy and hyperplasia via direct interaction with HDAC4. MC1568 treatment weakened the association between HDAC4 and CaMKIIα.
These results suggest that class II HDAC inhibition attenuates hypertension by negatively regulating VSMC hypertrophy and hyperplasia via the CaMKIIα/protein kinase D1/HDAC4/GATA6 pathway.
据报道，组蛋白去乙酰化酶（HDAC）抑制剂可改善原发性和继发性高血压。然而，可能作为治疗靶点的特定HDAC以及参与调节高血压的相关上游和下游分子仍不清楚。我们的研究旨在调查II类HDAC的选择性抑制剂（MC1568）是否能调节高血压，并阐明其潜在机制。
在用MC1568治疗前，通过给小鼠注射血管紧张素II（Ang II）来建立高血压模型。测量收缩压（SBP）。
MC1568治疗可降低升高的SBP；减轻肾小动脉和胸主动脉的动脉重塑；并在体内和体外抑制细胞周期调节基因表达、血管平滑肌细胞（VSMC）增殖、DNA合成及VSMC肥大。Ang II增强了磷酸化HDAC4和GATA结合因子6（GATA6）蛋白的表达，它们特异性定位于肾动脉和主动脉细胞的细胞质中。HDAC4的过表达和敲低分别增加和减少了VSMC中细胞周期基因的增殖和表达。GATA6是新发现的HDAC4结合伴侣，显著增加了VSMC的大小和数量。钙/钙调蛋白依赖性激酶IIα（CaMKIIα）而非HDAC4，在Ang II作用下从细胞核转位至细胞质。CaMKIIα和蛋白激酶D1通过与HDAC4直接相互作用，与VSMC肥大和增生相关。MC1568治疗减弱了HDAC4与CaMKIIα之间的关联。
这些结果表明，II类HDAC抑制通过CaMKIIα/蛋白激酶D1/HDAC4/GATA6途径负向调节VSMC肥大和增生，从而减轻高血压。
