Yunxing Xue1, Zhe Wei2, Hanying Ding2, Qiang Wang1, Zhen Zhou2, Shasha Zheng2, Yujing Zhang2, Dongxia Hou2, Yuchen Liu2, Ke Zen2, Chen-Yu Zhang2, Jing Li3, Dongjin Wang1, Xiaohong Jiang4. 1. Department of Thoracic and Cardiovascular Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China. 2. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences (NAILS), Nanjing University School of Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University, 22 Hankou Road, Nanjing 210093, Jiangsu, China. 3. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences (NAILS), Nanjing University School of Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University, 22 Hankou Road, Nanjing 210093, Jiangsu, China. Electronic address: jingli220@nju.edu.cn. 4. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences (NAILS), Nanjing University School of Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University, 22 Hankou Road, Nanjing 210093, Jiangsu, China. Electronic address: xiaohongjiang@nju.edu.cn.
Abstract
BACKGROUND: Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a master regulator of cellular energy metabolism that is associated with many cardiovascular diseases, including atherosclerosis. However, the role and underling regulatory mechanisms of PGC-1α in the pathogenesis of atherosclerosis are not completely understood. Here, we identified the microRNAs that post-transcriptionally regulate PGC-1α production and their roles in the pathogenesis of atherosclerosis. METHODS AND RESULTS: A significant down-regulation of PGC-1α protein was observed in human atherosclerotic vessel samples. Using microarray and bioinformatics analyses, PGC-1α was identified as a common target gene of miR-19b-3p, miR-221-3p and miR-222-3p, which are mainly located in the intima of atherosclerotic vessels. In vitro induction of miR-19b-3p, miR-221-3p and miR-222-3p by the inflammatory cytokines TNFα and IFNγ may affect PGC-1α protein production and consequently result in mitochondrial dysfunction in Human Aortic Endothelial Cells (HAECs). The overexpression of miR-19b-3p, miR-221-3p and miR-222-3p in HAECs caused intracellular ROS accumulation, which led to cellular apoptosis. CONCLUSION: Taken together, these results demonstrate that PGC-1α plays a protective role against the vascular complications of atherosclerosis. Moreover, the posttranscriptional regulation of PGC-1α by miR-19b/221/222 was unveiled, which provides a novel mechanism in which a panel of microRNAs can modulate endothelial cell apoptosis via the regulation mitochondrial function.
BACKGROUND: Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a master regulator of cellular energy metabolism that is associated with many cardiovascular diseases, including atherosclerosis. However, the role and underling regulatory mechanisms of PGC-1α in the pathogenesis of atherosclerosis are not completely understood. Here, we identified the microRNAs that post-transcriptionally regulate PGC-1α production and their roles in the pathogenesis of atherosclerosis. METHODS AND RESULTS: A significant down-regulation of PGC-1α protein was observed in humanatherosclerotic vessel samples. Using microarray and bioinformatics analyses, PGC-1α was identified as a common target gene of miR-19b-3p, miR-221-3p and miR-222-3p, which are mainly located in the intima of atherosclerotic vessels. In vitro induction of miR-19b-3p, miR-221-3p and miR-222-3p by the inflammatory cytokines TNFα and IFNγ may affect PGC-1α protein production and consequently result in mitochondrial dysfunction in Human Aortic Endothelial Cells (HAECs). The overexpression of miR-19b-3p, miR-221-3p and miR-222-3p in HAECs caused intracellular ROS accumulation, which led to cellular apoptosis. CONCLUSION: Taken together, these results demonstrate that PGC-1α plays a protective role against the vascular complications of atherosclerosis. Moreover, the posttranscriptional regulation of PGC-1α by miR-19b/221/222 was unveiled, which provides a novel mechanism in which a panel of microRNAs can modulate endothelial cell apoptosis via the regulation mitochondrial function.
Authors: Andrew O Kadlec; Dawid S Chabowski; Karima Ait-Aissa; Joseph C Hockenberry; Mary F Otterson; Matthew J Durand; Julie K Freed; Andreas M Beyer; David D Gutterman Journal: Hypertension Date: 2017-05-22 Impact factor: 10.190
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