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

Abstract

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.

Airway smooth muscle inflammation is regulated by microRNA‐145 in COPD

“…Interestingly, Hu et al . , have reported that activation of MEK‐1/2 suppresses miR‐145 expression in VSMCs, and Kent et al . , demonstrate that miR‐145 expression is inhibited through activation of the MAPK and JNK pathways in colorectal cancer.…”

Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation

“…Savage, unpublished observations). Among these, miR-9, miR-145, miR-214 and miR-499-5p have been linked to vascular and coronary function (Gidlöf et al, 2013; Hu et al, 2014; Jin et al, 2015; Shimizu et al, 2013; Turczy ska et al, 2012; Wang et al, 2010), and could be of interest because IL-33 from cardiac fibroblasts can promote cardioprotection (Sanada et al, 2007). …”

Mechanisms and therapeutic potential of microRNAs in hypertension

“…No study has elucidated the possible relationship between miRNA mechanisms and exercise-induced SMC phenotype changing. However, Hu et al have identified miRNA profiles in an altered SMC phenotype by mechanical stretching using microarray and have identified the central role of miR-145 in this process [181]. …”