Journal Article

miR‐145 attenuates phenotypic transformation of aortic vascular smooth muscle cells to prevent aortic dissection

Zhou, Hao, Li, Yu‐mei, Zhang, Li, Chen, Liang‐wan, He, Jian, Qiu, Zhi‐Huang, Zhang, Yu‐ling, Zheng, Hui, Chai, Tian‐ci, Chen, Xiao‐song

2021

Overview

Background miR‐145 is closely related to vascular smooth muscle cells (VSMC) phenotype transformation; however, the regulatory mechanisms through which miR‐145 regulates the VSMC phenotype transformation under mechanical stretching are unclear. In this study, we evaluated the roles of miR‐145 in VSMCs subjected to mechanical stretching in aortic dissection (AD). Methods The expression of miR‐145 in the aortic vessel wall of model animals and patients with AD was analyzed by quantitative polymerase chain reaction. miR‐145‐related protein‐protein interaction networks and Wikipathways were used to analyze VSMC phenotypic transformation pathways regulated by miR‐145. We used gain‐ and loss‐of‐function studies to evaluate the effects of miR‐145 on VSMC differentiation under mechanical stretch induction and assessed whether Krüppel‐like factor 4 (KLF4) was regulated by miR‐145 in the aorta under mechanical stretch conditions. Results miR‐145 was abundantly expressed in the walls of the normal human aorta, but was significantly downregulated in animal models and the walls of patients with dissection. We found that contractile phenotype‐related proteins were downregulated in VSMCs subjected to mechanical stretching, whereas the expression of secreted phenotype‐related proteins increased. miR‐145 overexpression also downregulated contractile phenotype‐related proteins in VSMCs and suppressed upregulation of phenotype‐related proteins. Finally, under mechanical stretching, KLF4 expression was significantly increased in VSMCs, and overexpression of miR‐145 blocked this effect. Conclusion Our results confirmed that mechanical stretch‐induced phenotypic transformation of VSMCs to promote AD via upregulation of KLF4; this mechanism was regulated by miR‐145, which directly modulated KLF4 expression and VSMC differentiation. miR‐145 was abundantly expressed in the walls of the normal human aorta, but was significantly downregulated in animal models and the walls of patients with dissection. Contractile phenotype‐related proteins were downregulated in VSMCs subjected to mechanical stretching, whereas the expression of secreted phenotype‐related proteins increased. Mechanical stretch induced phenotypic transformation of VSMCs to promote AD via upregulation of KLF4. This mechanism was regulated by miR‐145, which directly modulated KLF4 expression and VSMC differentiation.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Animal models / Animals / Antibodies / Aorta / Aortic dissection / Aortic Dissection - genetics / Aortic Dissection - pathology / Biomechanical Phenomena / Cell culture / Cell Differentiation - genetics / Cells, Cultured / Coronary vessels / Disease Models, Animal / Dissection / Drinking water / Gene Expression Regulation / Genetic transformation / Humans / Hydrochloric acid / KLF4 protein / Kruppel-Like Factor 4 - genetics / Laboratory animals / Male / Matrix Metalloproteinase 9 - metabolism / Mechanical properties / mechanical strain / Membranes / MicroRNAs - genetics / miR145 / Muscle contraction / Muscle, Smooth, Vascular - pathology / Muscle, Smooth, Vascular - physiology / Phenotype / phenotype transformation / Phenotypes / Polymerase chain reaction / Protein Interaction Maps - genetics / Proteins / Rats / Rats, Sprague-Dawley / Silicones / Smooth muscle / Transplants & implants / vascular smooth muscle cells