Abstract 12453: Smooth Muscle-Specific Latexin Deficiency Prevents Platelet-Derived Growth Factor-Mediated Vascular Smooth Muscle Cell Phenotypic Switch and Neointimal Formation

Abstract

Introduction: Vascular smooth muscle cell (SMC) phenotypic switch from a contractile to a synthetic phenotype plays a significant role in vascular pathologies, including atherosclerosis, restenosis, and aneurysm. Latexin (LXN) is a novel inflammatory protein that is highly expressed in SMCs; the role of LXN in SMCs biology, however, remains largely unknown. Methods: Both global and SMC-specific LXN-knockout mice were generated to determine the in vivo function of LXN in SMC remolding. Neointimal formation induced by mouse carotid artery ligation was assessed by HE staining. Mouse SMCs were isolated from thoracic aortas and used for biological and functional assays. Western blot (WB), immunohistochemistry (IHC), RNA-seq, and quantitative polymerase chain reaction (qPCR) were used to assess protein and gene expression. BrdU incorporation assay and Boyden’s chamber assay were used to assess SMC proliferation and migration. Results: The expression of contractile SMC markers were down-regulated, while synthetic SMC markers were up-regulated in the mouse model of carotid artery ligation. LXN expression was significantly increased in mouse carotid arteries after ligation-induced injury. Furthermore, we found that both global and SMC-specific deletion of LXN significantly attenuated neointimal formation after injury, implicating an essential role of LXN in the modulation of SMC phenotype. Our ex vivo and in vitro functional assays showed that LXN deficiency attenuates SMC proliferation and migration, which is consistent with our RNA-seq data showing that the expression of cell proliferation-related genes was down-regulated in LXN deficient mouse SMCs. Mechanistically, we identified platelet-derived growth factor receptor alpha as a critical mediator involved in regulating SMC phenotypic switch by LXN. Conclusions: Our results for the first time identify LXN as a critical mediator in regulating SMC phenotypic switch and suggest that inhibition of LXN may represent a novel therapeutic strategy for the treatment of proliferative vascular diseases such as atherosclerosis and restenosis.