AMP-Activated Protein Kinase Regulates Endothelial Cell Angiotensin-Converting Enzyme Expression via p53 and the Post-Transcriptional Regulation of microRNA-143/145

作者：Kohlstedt Karin; Trouvain Caroline; Boettger Thomas; Shi Lei; Fisslthaler Beate; Fleming Ingrid^*

来源：Circulation Research, 2013, 112(8): 1150-+.

DOI：10.1161/CIRCRESAHA.113.301282

• angiotensin-converting enzyme
• diabetes
• microRNA

Rationale: High-angiotensin-converting enzyme (ACE)-levels are associated with cardiovascular disease, but little is known about the regulation of its expression. %26lt;br%26gt;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. %26lt;br%26gt;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. %26lt;br%26gt;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.)

• 出版日期2013-4-12