Hoshun Chong1, Zhe Wei2, Muhan Na2, Gongrui Sun2, Shasha Zheng2, Xiyu Zhu3, Yunxing Xue3, Qing Zhou3, Shanjun Guo2, Jinhong Xu2, Haoquan Wang2, Le Cui2, Chen-Yu Zhang2, Xiaohong Jiang4, Dongjin Wang5. 1. State Key Laboratory of Pharmaceutical Biotechnology, Department of Thoracic and Cardiovascular Surgery, Nanjing Drum Tower Hospital, Medical School of Nanjing University, China; State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, China. 2. State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, China. 3. State Key Laboratory of Pharmaceutical Biotechnology, Department of Thoracic and Cardiovascular Surgery, Nanjing Drum Tower Hospital, Medical School of Nanjing University, China. 4. State Key Laboratory of Pharmaceutical Biotechnology, Department of Thoracic and Cardiovascular Surgery, Nanjing Drum Tower Hospital, Medical School of Nanjing University, China; State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, China. Electronic address: xiaohongjiang@nju.edu.cn. 5. State Key Laboratory of Pharmaceutical Biotechnology, Department of Thoracic and Cardiovascular Surgery, Nanjing Drum Tower Hospital, Medical School of Nanjing University, China; State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, China; Institute of Cardiothoracic Vascular Disease, Nanjing University, China. Electronic address: 15298387214@163.com.
Abstract
BACKGROUND AND AIMS: Atherosclerosis (AS) is the leading cause of cardiovascular diseases. PGC-1α is a key regulator of cellular energy homeostasis, but its role in AS remains debatable. METHODS AND RESULTS: In our study, PGC-1α was shown to be significantly decreased in the media of human atherosclerotic vessels. To explore whether miRNAs might be regulated by PGC-1α in vascular smooth muscle cells (VSMCs), microarray analysis was performed. Microarray and Pearson's correlation analysis showed that PGC-1α and miR-378a were positively correlated in vivo and in vitro. As an upstream co-activator, PGC-1α was found to regulate miR-378a through binding to the transcriptional factor NRF1 in VSMCs. Therefore, the decreased expression of PGC-1α might account for suppression of miR-378a in VSMCs in AS. Furthermore, IGF1 and TLR8, two genes known to be aberrantly up-regulated in atherogenic vessels, were identified as direct targets of miR-378a. In vitro up-regulation of miR-378a markedly inhibited free fatty acid (FFA)-induced VSMC proliferation, migration and inflammation through targeting IGF1 and TLR8. CONCLUSIONS: These findings highlight the protective role of the PGC-1α/NRF1/miR-378a regulatory axis in AS progression and suggest miR-378a as potential therapeutic target for AS treatment.
BACKGROUND AND AIMS: Atherosclerosis (AS) is the leading cause of cardiovascular diseases. PGC-1α is a key regulator of cellular energy homeostasis, but its role in AS remains debatable. METHODS AND RESULTS: In our study, PGC-1α was shown to be significantly decreased in the media of humanatherosclerotic vessels. To explore whether miRNAs might be regulated by PGC-1α in vascular smooth muscle cells (VSMCs), microarray analysis was performed. Microarray and Pearson's correlation analysis showed that PGC-1α and miR-378a were positively correlated in vivo and in vitro. As an upstream co-activator, PGC-1α was found to regulate miR-378a through binding to the transcriptional factor NRF1 in VSMCs. Therefore, the decreased expression of PGC-1α might account for suppression of miR-378a in VSMCs in AS. Furthermore, IGF1 and TLR8, two genes known to be aberrantly up-regulated in atherogenic vessels, were identified as direct targets of miR-378a. In vitro up-regulation of miR-378a markedly inhibited free fatty acid (FFA)-induced VSMC proliferation, migration and inflammation through targeting IGF1 and TLR8. CONCLUSIONS: These findings highlight the protective role of the PGC-1α/NRF1/miR-378a regulatory axis in AS progression and suggest miR-378a as potential therapeutic target for AS treatment.