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: Kou-Gi Shyu, Wen-Ping Cheng, Bao-Wei Wang
• Journal: Molecular medicine (Cambridge, Mass.) (Mol Med) Vol. 21 Pg. 616-25 (Jul 14 2015) ISSN: 1528-3658 [Electronic] England
• PMID: 26181633 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• KLF4 protein, human
• Klf4 protein, rat
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors
• MIRN145 microRNA, human
• MicroRNAs
• Nuclear Proteins
• Trans-Activators
• myocardin
• Angiotensin II
• Valsartan
• Glucose

Topics

• Angiotensin II (genetics)
• Animals
• Cell Proliferation (drug effects)
• Cells, Cultured
• Coronary Vessels (drug effects, pathology)
• Gene Expression Regulation (drug effects)
• Glucose (pharmacology)
• Humans
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors (biosynthesis)
• MicroRNAs (biosynthesis, genetics)
• Muscle, Smooth, Vascular
• Myocytes, Smooth Muscle (drug effects, pathology)
• Nuclear Proteins (biosynthesis)
• Rats
• Trans-Activators (biosynthesis)
• Tunica Media (metabolism, pathology)
• Valsartan (administration & dosage)