HDAC1-mediated deacetylation of HIF1α prevents atherosclerosis progression by promoting miR-224-3p-mediated inhibition of FOSL2
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) deac...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-03-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253120303565 |
| _version_ | 1818442233978814464 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Hao Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T18:40:54Z |
| format | Article |
| id | doaj.art-4d9de16a957d4d28aa7bd099fb3784da |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-14T18:40:54Z |
| publishDate | 2021-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-4d9de16a957d4d28aa7bd099fb3784da2022-12-21T22:51:30ZengElsevierMolecular Therapy: Nucleic Acids2162-25312021-03-0123577591HDAC1-mediated deacetylation of HIF1α prevents atherosclerosis progression by promoting miR-224-3p-mediated inhibition of FOSL2Hao Wang0Kazuo Sugimoto1Hao Lu2Wan-Yong Yang3Ji-Yue Liu4Hong-Yu Yang5Yue-Bo Song6Dong Yan7Tian-Yu Zou8Si Shen9Stroke Center, the First Affiliated Hospital, Jinan University, Guangzhou 510630, P.R. China; Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, Chiba 260-8670, JapanDepartment of Neurology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, P.R. China; Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, Chiba 260-8670, JapanStroke Center, the First Affiliated Hospital, Jinan University, Guangzhou 510630, P.R. ChinaStroke Center, the First Affiliated Hospital, Jinan University, Guangzhou 510630, P.R. ChinaStroke Center, the First Affiliated Hospital, Jinan University, Guangzhou 510630, P.R. ChinaStroke Center, the First Affiliated Hospital, Jinan University, Guangzhou 510630, P.R. ChinaDepartment of Neurology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, P.R. ChinaDepartment of Neurology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, P.R. ChinaDepartment of Encephalopathy, Heilongjiang Academy of Chinese Medical Sciences, Harbin 150001, P.R. ChinaStroke Center, the First Affiliated Hospital, Jinan University, Guangzhou 510630, P.R. China; Corresponding author: Si Shen, Stroke Center, the First Affiliated Hospital, Jinan University, No. 613, West Huangpu Avenue, Tianhe District, Guangzhou 510630, P.R. China.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.http://www.sciencedirect.com/science/article/pii/S2162253120303565HDAC1HIF1αmiR-224-3pFOSL2atherosclerosisendothelial cell apoptosis |
| spellingShingle | 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 HDAC1-mediated deacetylation of HIF1α prevents atherosclerosis progression by promoting miR-224-3p-mediated inhibition of FOSL2 Molecular Therapy: Nucleic Acids HDAC1 HIF1α miR-224-3p FOSL2 atherosclerosis endothelial cell apoptosis |
| title | HDAC1-mediated deacetylation of HIF1α prevents atherosclerosis progression by promoting miR-224-3p-mediated inhibition of FOSL2 |
| title_full | HDAC1-mediated deacetylation of HIF1α prevents atherosclerosis progression by promoting miR-224-3p-mediated inhibition of FOSL2 |
| title_fullStr | HDAC1-mediated deacetylation of HIF1α prevents atherosclerosis progression by promoting miR-224-3p-mediated inhibition of FOSL2 |
| title_full_unstemmed | HDAC1-mediated deacetylation of HIF1α prevents atherosclerosis progression by promoting miR-224-3p-mediated inhibition of FOSL2 |
| title_short | HDAC1-mediated deacetylation of HIF1α prevents atherosclerosis progression by promoting miR-224-3p-mediated inhibition of FOSL2 |
| title_sort | hdac1 mediated deacetylation of hif1α prevents atherosclerosis progression by promoting mir 224 3p mediated inhibition of fosl2 |
| topic | HDAC1 HIF1α miR-224-3p FOSL2 atherosclerosis endothelial cell apoptosis |
| url | http://www.sciencedirect.com/science/article/pii/S2162253120303565 |
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