Mechanical stretch suppresses microRNA-145 expression by activating extracellular signal-regulated kinase 1/2 and upregulating angiotensin-converting enzyme to alter vascular smooth muscle cell phenotype.
Phenotype modulation of vascular smooth muscle cells (VSMCs) plays an important role in the pathogenesis of various vascular diseases, including hypertension and atherosclerosis. Several microRNAs (miRNAs) were found involved in regulating the VSMC phenotype with platelet-derived growth factor (PDGF) treatment, but the role of miRNAs in the mechanical stretch-altered VSMC phenotype is not clear. Here, we identified miR-145 as a major miRNA contributing to stretch-altered VSMC phenotype by miRNA array, quantitative RT-PCR and gain- and loss-of-function methods. Our data demonstrated that 16% stretch suppressed miR-145 expression, with reduced expression of contractile markers of VSMCs cultured on collagenI; overexpression of miR-145 could partially recover the expression in stretched cells. Serum response factor (SRF), myocardin, and Kruppel-like factor 4 (KLF4) are major regulators of the VSMC phenotype. The effect of stretch on myocardin and KLF4 protein expression was altered by miR-145 mimics, but SRF expression was not affected. In addition, stretch-activated extracellular signal-regulated kinase 1/2 (ERK1/2) and up-regulated angiotensin-converting enzyme (ACE) were confirmed to be responsible for the inhibition of miR-145 expression. Mechanical stretch inhibits miR-145 expression by activating the ERK1/2 signaling pathway and promoting ACE expression, thus modulating the VSMC phenotype.
Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
Bo
B
Hu
Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
Jian Tao
JT
Song
Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
Hai Yan
HY
Qu
Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
Chen Long
CL
Bi
Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
Xiao Zhen
XZ
Huang
Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
Xin Xin
XX
Liu
Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
Mei
M
Zhang
D001696:Biomechanical Phenomena; D002478:Cells, Cultured; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000201:enzymology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D010641:Phenotype; D034622:RNA Interference; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000099251:Myocardin
D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009687:Nuclear Proteins; D007703:Peptidyl-Dipeptidase A; D015534:Trans-Activators; D000099251:Myocardin; C000715467:KLF4 protein, human; C541010:MIRN145 microRNA, human; C535150:MAPK1 protein, human