Research Papers: Pathology:
Lovastatin upregulates microRNA-29b to reduce oxidative stress in rats with multiple cardiovascular risk factors
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Fu Wang1, Hui Ma1, Wen-Jing Liang1, Jing-Jing Yang1, Xue-Qing Wang1, Mei-Rong Shan1, Yuan Chen1, Min Jia2, Ya-Ling Yin3, Xue-Ying Sun4, Jia-Ning Zhang5, Qi-Sheng Peng6, Yu-Guo Chen1, Li-Ying Liu4, Peng Li3, Tao Guo1 and Shuang-Xi Wang1
1 The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University School of Medicine, Jinan, China
2 Department of Rehabilitation Medicine, Jinan Municipal Hospital of Traditional Chinese Medicine, Jinan, China
3 Department of Pharmacology, College of Pharmacy, Xinxiang Medical University, Xinxiang, China
4 Department of Pharmacology, Pharmaceutical College, Central South University, Changsha, China
5 Biology and Chemistry, Denison University, Granville, OH, USA
6 Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun, China
Shuang-Xi Wang, email:
Tao Guo, email:
Peng Li, email:
Keywords: lovastatin, microRNA-29b, oxidative stress, PA200, endothelial dysfunction, Pathology Section
Received: June 03, 2016 Accepted: September 25, 2016 Published: January 03, 2017
Aims: Proteasome-linked oxidative stress is believed to cause endothelial dysfunction, an early event in cardiovascular diseases (CVD). Statin, as HMG-CoA reductase inhibitor, prevents endothelial dysfunction in CVD. However, the molecular mechanism of statin-mediated normalization of endothelial function is not completely elucidated. Methods and Results: Lovastatin time/dose-dependently increased miR-29b expression and decreased proteasome activity in cultured human umbilical vein endothelial cells (HUVECs). Anti-miR-29b or overexpression of PA200 abolished lovastatin-induced inhibition of proteasome activity in HUVECs. In contrast, pre-miR-29b or PA200 siRNA mimics these effects of lovastatin on proteasome activity. Lovastatin inhibited oxidative stress induced by multiple oxidants including ox-LDL, H2O2, TNFα, homocysteine thiolactone (HTL), and high glucose (HG), which were reversed by inhibition of miR-29b in HUVECs. Ex vivo analysis indicated that lovastatin normalized the acetylcholine-induced endothelium-dependent relaxation and the redox status in isolated rat aortic arteries exposure to multiple cardiovascular risk factors. In vivo analysis revealed that administration of lovastatin remarkably suppressed oxidative stress and prevented endothelial dysfunction in rats with hyperglycemia, dyslipidemia, and hyperhomocysteinemia, as well as increased miR-29b expressions, reduced PA200 protein levels, and suppression of proteasome activity in aortic tissues. Conclusion: Upregulation of miR-29b expression is a common mechanism contributing to endothelial dysfunction induced by multiple cardiovascular risk factors through PA200-dependent proteasome-mediated oxidative stress, which is prevented by lovastatin.
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