Lovastatin upregulates microRNA-29b to reduce oxidative stress in rats with multiple cardiovascular risk factors.

Fu Wang,Yuan Chen,Mei-Rong Shan,Yu-Guo Chen,Jia-Ning Zhang,Qi-Sheng Peng,Xue-Qing Wang,Xue-Ying Sun,Shuang-Xi Wang,Jing-Jing Yang,Min Jia,Tao Guo,Peng Li,Li-Ying Liu,Wen-Jing Liang,Hui Ma,Ya-Ling Yin

doi:10.18632/oncotarget.14462

Abstract

AimsProteasome-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 ResultsLovastatin 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, TNFa, 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.ConclusionUpregulation 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.

Highlights

Lovastatin is used for the treatment of hypercholesterolemia because it inhibits HMG-CoA reductase, and prevents HMG-CoA’s conversion into mevalonic acid [1]
We have defined a common mechanism of lovastatin to prevent endothelial dysfunction in different models of cardiovascular diseases (CVD), in which lovastatin-increased miR-29b expression is linked to the suppression of oxidative stress, a key step to cause endothelial dysfunction in CVD
To the best of our knowledge, this is the first report on the impacts of statin on endothelial dysfunction in multiple animal models with risk factors of cardiovascular disease

Summary

Introduction

Lovastatin is used for the treatment of hypercholesterolemia because it inhibits HMG-CoA reductase, and prevents HMG-CoA’s conversion into mevalonic acid [1]. Oxidative stress is believed to cause endothelial dysfunction, an early event and a hallmark in CVD, including atherosclerosis and hypertension [24]. At this standpoint, it is widely accepted that statins www.impactjournals.com/oncotarget prevent endothelial dysfunction by decreasing oxidative stress in vascular cells. The targets for stainreduced oxidative stress in CVD have not been completely elucidated. Our and other’s previous studies have proven that activation of proteasome links to oxidative stress and consequent endothelial dysfunction in CVD [4,5,6]. Proteasomes are responsible for the degradation of a large number of protein targets throughout eukaryotic cells. As one of proteasome activators (PAs), PA200 is broadly expressed in mammalian tissues and it has been suggested to play a crucial role in response to DNA damage [7, 8]

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Conclusion