Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, 826, Zhangheng Road, Pudong New District, Shanghai 201203, PR China.
State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China.
Cardiovasc Res. 2018 Jun 1;114(7):1016-1028. doi: 10.1093/cvr/cvy051.
Angiotensin II (Ang II) causes vascular inflammation, leading to vascular endothelial cell dysfunction, and is associated with the development of cardiovascular diseases. Therefore, interventions in inflammation may contribute to the reduction of cardiovascular diseases. Here, we aim to demonstrate that HDAC4, one of class IIa family histone de-acetylases (HDACs) members, promotes autophagy-dependent vascular inflammation.
By loss-of-function approaches, our study provides the first evidence that HDAC4 mediates Ang II-induced vascular inflammation in vitro and in vivo. In response to the Ang II, HDAC4 expression is up-regulated rapidly, with increased autophagic flux and inflammatory mediators in vascular endothelial cells (VECs). In turn, HDAC4 deficiency suppresses activation of autophagy, leading to reduced inflammation in Ang II-induced VECs. Consistently, using autophagy inhibitor or silencing LC3-II also alleviates vascular inflammation. Furthermore, HDAC4 regulates autophagy via facilitating transcription factor forkhead box O3a (FoxO3a) de-acetylation, thereby to increase its transcriptional activity. Loss of HDAC4 in VECs results in inhibition of FoxO3a de-acetylation to block its transcriptional activity, leading to downregulation of the downstream FoxO3a target, and hence reduces autophagy and vascular inflammation. FoxO3a silencing using siRNA approach significantly inhibits activation of autophagy. Finally, knockdown of HDAC4 in Ang II-infused mouse models ameliorates vascular inflammation, suggesting that inhibitor of HDAC4 may be potential therapeutics for vascular diseases associated with inflammation.
These results suggest that HDAC4-mediated FoxO3a acetylation regulates Ang II-induced autophagy activation, which in turn plays an essential role in causing vascular inflammation.
血管紧张素 II（Ang II）引起血管炎症，导致血管内皮细胞功能障碍，与心血管疾病的发展有关。因此，干预炎症可能有助于减少心血管疾病。在这里，我们旨在证明 HDAC4（IIa 类组蛋白去乙酰化酶（HDACs）家族成员之一）促进自噬依赖性血管炎症。
通过功能丧失方法，我们的研究首次提供了证据，证明 HDAC4 介导了体外和体内 Ang II 诱导的血管炎症。对 Ang II 的反应中，HDAC4 表达迅速上调，血管内皮细胞（VECs）中的自噬通量和炎症介质增加。反过来，HDAC4 缺乏抑制自噬的激活，导致 Ang II 诱导的 VEC 中炎症减少。一致地，使用自噬抑制剂或沉默 LC3-II 也可减轻血管炎症。此外，HDAC4 通过促进转录因子叉头框 O3a（FoxO3a）去乙酰化来调节自噬，从而增加其转录活性。VECs 中 HDAC4 的缺失导致 FoxO3a 去乙酰化的抑制，从而阻断其转录活性，导致下游 FoxO3a 靶标的下调，从而减少自噬和血管炎症。使用 siRNA 方法沉默 FoxO3a 可显著抑制自噬的激活。最后，在 Ang II 输注的小鼠模型中敲低 HDAC4 可改善血管炎症，表明 HDAC4 抑制剂可能是与炎症相关的血管疾病的潜在治疗方法。
这些结果表明，HDAC4 介导的 FoxO3a 乙酰化调节 Ang II 诱导的自噬激活，进而在引起血管炎症中发挥重要作用。
