Polycystin-1 Downregulation Induces Aortic Vascular Smooth Muscle Cells Phenotypic Alteration and Extracellular Matrix Dysfunction in Thoracic Aortic Dissection

Abstract

Polycystin (PC)-1 is a transmembrane protein encoded by the gene of polycystic kidney disease-1 (PKD-1), which regulates cellular proliferation and migration. This study was designed to investigate the regulatory mechanisms of PC-1 on phenotypes of aortic vascular smooth muscle cells (VSMCs) and functions of extracellular matrix (ECM) in thoracic aortic dissection (TAD). In this work, aortic tissues from patients with TAD and healthy controls were collected, in vitro studies were also performed. Compared with the control group, expression of PC-1 and the contractile phenotypic markers of VSMCs were significantly decreased in TAD group, whereas expression of the synthetic markers of VSMCs, matrix metalloproteinase (MMP)-2, collagen I and collagen III were increased. The phosphorylation of mTOR, S6K and S6 were also elevated in TAD group. PC-1 downregulation of aortic VSMCs inhibited the expression of the contractile markers, but elevated the expression of the synthetic markers, MMP-2, collagen I and collagen III compared with the control group. The phosphorylation of mTOR, S6K and S6 were also increased in PKD-1-knockdwon VSMCs. PC-1 upregulation reversed all these expression characteristics in aortic VSMCs. Furthermore, rapamycin treatment to PKD-1-knockdwon VSMCs inhibited the effects caused by PC-1 downregulation. These results of our study have revealed that PC-1 downregulation induces aortic VSMCs phenotypic alteration and ECM dysfunction via activation of mTOR/S6K/S6 signaling pathway, thus the downregulation of PC-1 might be a potential mechanism for the development and progression of TAD. Funding Statement: This study was supported by National Natural Science Foundation of China (81700422 to Jing Zhang, 81570438, 81970412 to Li-xin Wang), Shanghai Science and Technology Foundation (14YF1412600 to Jing Zhang, 18441902400 to Li-xin Wang) and Shanghai Chest Hospital Project of Collaborative Innovation (YJXT20190207 to Jing Zhang). Declaration of Interests: The authors stated: None. Ethics Approval Statement: The collection and use of human aortic samples were approved by the Ethical Committee of Shanghai Chest Hospital.