title: Angiotensin II Downregulates MicroRNA-145 to Regulate Kruppel-like Factor 4 and Myocardin Expression in Human Coronary Arterial Smooth Muscle Cells under High Glucose Conditions.
abstract: MicroRNA (miR)-145 is the most abundant miR in vascular smooth muscle cells (VSMCs). However, the effect of hyperglycemia on the regulation of miR-145 is unknown. We hypothesized that the hyperglycemic condition activates a proinflammatory response that mediates the expression of miR-145 in VSMCs. We investigated whether miR-145 serves as a critical regulator to regulate the downstream proliferation factors (including Kruppel-like factor 4 [Klf4] and myocardin) in VSMCs under hyperglycemic conditions. Human coronary artery smooth muscle cells (HCASMCs) were cultured under high glucose conditions. Sustained high glucose at 25 mmol/L significantly decreased the expression of miR-145 in HCASMCs. High glucose significantly increased angiotensin II (Ang II) secretion from HCASMCs and Ang II suppressed miR-145 expression in HCASMCs. Ang II repression of miR145 expression resulted in increased Klf4 and decreased myocardin expression under conditions of high glucose. Overexpression of miR-145 significantly decreased Klf4 and increased myocardin expression and inhibited HCASMC proliferation and migration induced by a high glucose state. Balloon injury of the carotid artery in diabetic rats was performed to investigate miR-145, Klf and myocardin expression. The expression of miR-145 was maximally increased at 7 d after carotid injury and gradually declined thereafter. Overexpression of miR-145 and treatment with valsartan reversed Klf4 and myocardin protein expression induced by balloon injury and improved vascular injury. In conclusion, our study reveals that Ang II downregulates miR-145 to regulate Klf4 and myocardin expression in HCASMCs under high glucose conditions. Ang II plays a critical role in the regulation of miR-145 under hyperglycemic conditions.
authors.affiliation: Division of Cardiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.|Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Kou-Gi
authors.initials: KG
authors.lastname: Shyu
authors.affiliation: Department of Medical Education and Research, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Wen-Ping
authors.initials: WP
authors.lastname: Cheng
authors.affiliation: Department of Medical Education and Research, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Bao-Wei
authors.initials: BW
authors.lastname: Wang
mesh_terms: D000804:Angiotensin II / Q000235:genetics*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis*; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009131:Muscle, Smooth, Vascular; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis*; D051381:Rats; D015534:Trans-Activators / Q000096:biosynthesis*; D017540:Tunica Media / Q000378:metabolism / Q000473:pathology; D000068756:Valsartan / Q000008:administration & dosage; D000099251:Myocardin
chemical_list: D000804:Angiotensin II; D005947:Glucose; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; D009687:Nuclear Proteins; D015534:Trans-Activators; D000068756:Valsartan; D000099251:Myocardin; C000715467:KLF4 protein, human; C000715469:Klf4 protein, rat; C541010:MIRN145 microRNA, human