Abstract P1018: Peptidyl-prolyl Cis-trans Isomerase-like 4 Is A Novel Regulator Of Smooth Muscle Cell Remodeling

Abstract

Introduction: Smooth muscle cell (SMC) remodeling is a complex and multifaceted process that plays an essential role in the maintenance and function of various organ systems in the body. In response to physiological and pathological stimuli, smooth muscle cells exhibit remarkable plasticity, undergoing morphological and functional changes that can impact vascular tone. Dysregulation of SMC remodeling can contribute to the development and progression of numerous pathological conditions, such as hypertension and atherosclerosis. However, the role of SMC remodeling in intracranial aneurysm (IA) formation has yet to be explored. Objective-Method: In this study, we aimed to elucidate the role of PPIL4, an IA-implicated gene, in SMC remodeling using a targeted experimental approach. We performed immunostaining and bulk RNA sequencing (RNA-seq) in human primary brain vascular smooth muscle cells (HPBVSMC) treated with lentiviral shRNA and open-reading-frame (ORF) particles to individually downregulate and overexpress PPIL4, respectively. Results: We found that PPIL4 downregulation results in significant upregulation of the genes encoding contractile proteins, including ACTA2, CNN1, TNNT1, and TNNT2, in HPBVSMC and leads to a significantly increased cell size, favoring a contractile SMC phenotype. Conversely, overexpressing PPIL4 using ORF-lentiviral particles caused downregulation of contractile proteins, increased expression of MMP1 and MMP3, and promoted a synthetic phenotype in SMCs. Furthermore, PPIL4 overexpression caused cell elongation and spindle-like cell formation in HPBVSMC. Conclusion: In conclusion, our findings highlight the critical role of PPIL4 in modulating SMC remodeling, suggesting a potential mechanistic link between PPIL4 dysregulation, SMC remodeling, and IA formation, which warrants further investigation.