期刊
CIRCULATION RESEARCH
卷 112, 期 8, 页码 1150-+出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.113.301282
关键词
angiotensin-converting enzyme; diabetes; microRNA
资金
- Deutsche Forschungsgemeinschaft [FL364/2-2, SFB834/A5]
- Deutsche Forschungsgemeinschaft (Exzellenzcluster 147 Cardio-Pulmonary Systems)
Rationale: High-angiotensin-converting enzyme (ACE)-levels are associated with cardiovascular disease, but little is known about the regulation of its expression. Objective: To assess the molecular mechanisms regulating endothelial ACE expression focusing on the role of the AMP-activated protein kinase (AMPK) and miR-143/145. Methods and Results: Shear stress decreased ACE expression in cultured endothelial cells, an effect prevented by downregulating AMPK alpha 2 but not AMPK alpha 1. AMPK alpha 2(-/-) mice expressed higher ACE levels than wild-type littermates resulting in impaired hindlimb vasodilatation to the ACE substrate, bradykinin. The latter response was also evident in animals lacking the AMPK alpha 2 subunit only in endothelial cells. In cultured endothelial cells, miR-143/145 levels were increased by shear stress in an AMPK alpha 2-dependent manner, and miR-143/145 overexpression decreased ACE expression. The effect of shear stress was unrelated to an increase in miR-143/145 promoter activity and transcription but could be attributed to post-transcriptional regulation of precursor-miR-143/145 by AMPK alpha 2. The AMPK substrate, p53, can enhance the post-transcriptional processing of several microRNAs, including miR-143/145. We found that shear stress elicited the AMPK alpha 2-dependent phosphorylation of p53 (on Ser15), and that p53 downregulation prevented the shear stress-induced decrease in ACE expression. Streptozotocin-induced diabetes mellitus in mice was studied as a pathophysiological model of altered AMPK activity. Diabetes mellitus increased tissue phosphorylation of the AMPK substrates, p53 and acetyl-coenzyme A carboxylase, changes that correlated with increased miR-143/145 levels and decreased ACE expression. Conclusions: AMPK alpha 2 suppresses endothelial ACE expression via the phosphorylation of p53 and upregulation of miR-143/145. Post-transcriptional regulation of miR-143/145 may contribute to the vascular complications associated with diabetes mellitus. (Circ Res. 2013; 112: 1150-1158.)
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