HDAC1-mediated deacetylation of HIF1α prevents atherosclerosis progression by promoting miR-224-3p-mediated inhibition of FOSL2

Hao Wang; Kazuo Sugimoto; Hao Lu; Wan-Yong Yang; Ji-Yue Liu; Hong-Yu Yang; Yue-Bo Song; Dong Yan; Tian-Yu Zou; Si Shen

doi:10.1016/j.omtn.2020.10.044

HDAC1-mediated deacetylation of HIF1α prevents atherosclerosis progression by promoting miR-224-3p-mediated inhibition of FOSL2

Mol Ther Nucleic Acids. 2020 Nov 5:23:577-591. doi: 10.1016/j.omtn.2020.10.044. eCollection 2021 Mar 5.

Authors

Hao Wang^{1

2}, Kazuo Sugimoto^{3

2}, Hao Lu¹, Wan-Yong Yang¹, Ji-Yue Liu¹, Hong-Yu Yang¹, Yue-Bo Song³, Dong Yan³, Tian-Yu Zou⁴, Si Shen¹

Affiliations

¹ Stroke Center, the First Affiliated Hospital, Jinan University, Guangzhou 510630, P.R. China.
² Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
³ Department of Neurology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, P.R. China.
⁴ Department of Encephalopathy, Heilongjiang Academy of Chinese Medical Sciences, Harbin 150001, P.R. China.

Abstract

We intended to characterize functional relevance of microRNA (miR)-224-3p in endothelial cell (EC) apoptosis and reactive oxygen species (ROS) accumulation in atherosclerosis, considering also the integral involvement of histone deacetylase 1 (HDAC1)-mediated hypoxia-inducible factor-1α (HIF1α) deacetylation. The binding affinity between miR-224-3p and Fos-like antigen 2 (FOSL2) was predicted and validated. Furthermore, we manipulated miR-224-3p, FOSL2, HDAC1, and HIF1α expression in oxidized low-density lipoprotein (ox-LDL)-induced ECs, aiming to clarify their effects on cell activities, inflammation, and ROS level. Additionally, we examined the impact of miR-224-3p on aortic atherosclerotic plaque and lesions in a high-fat-diet-induced atherosclerosis model in ApoE^-/- mice. Clinical atherosclerotic samples and ox-LDL-induced human aortic ECs (HAECs) exhibited low HDAC1/miR-224-3p expression and high HIF1α/FOSL2 expression. miR-224-3p repressed EC cell apoptosis, inflammatory responses, and intracellular ROS levels through targeting FOSL2. HIF1α reduced miR-224-3p expression to accelerate EC apoptosis and ROS accumulation. Moreover, HDAC1 inhibited HIF1α expression by deacetylation, which in turn enhanced miR-224-3p expression to attenuate EC apoptosis and ROS accumulation. miR-224-3p overexpression reduced atherosclerotic lesions in vivo. In summary, HDAC1 overexpression may enhance the anti-atherosclerotic and endothelial-protective effects of miR-224-3p-mediated inhibition of FOSL2 by deacetylating HIF1α, underscoring a novel therapeutic insight against experimental atherosclerosis.

Keywords: FOSL2; HDAC1; HIF1α; atherosclerosis; endothelial cell apoptosis; miR-224-3p; reactive oxygen species.