La Ribonucleoprotein 7 Protects Vascular Smooth Muscle Cell Contractile Phenotype in CKD by Coupling with P300

Key Points La ribonucleoprotein 7 (LARP7) acted as a positive regulator of vascular smooth muscle cell (VSMC) contractile phenotype by orchestrating P300-mediated H3K27 acetylation at contractile gene promoters. CKD microenvironment impaired the LARP7-P300 interaction, promoting VSMC transdifferentiation into osteogenic and inflammatory phenotypes. Restoration of LARP7 in CKD VSMCs reversed their phenotype switching and attenuated vascular calcification and atherosclerosis. Background Loss of vascular smooth muscle cell (VSMC) contractile phenotype complicates CKD and associates with cardiovascular pathologies. Here, focusing on vascular calcification and atherosclerosis, we tested the role of La ribonucleoprotein 7 (LARP7) in maintaining VSMC contractile phenotype and mitigating CKD-associated vascular pathologies. Methods Single-cell RNA sequencing and immunostaining analysis were used to investigate the association between LARP7 and contractile phenotype in VSMCs from patients with CKD. In vivo and in vitro models evaluated the expression profile of LARP7 in CKD and its contribution to VSMC dedifferentiation and progression of vascular calcification and atherosclerosis. Results We demonstrated that LARP7, abundantly expressed in normal VSMCs, was downregulated in patients with CKD, associated with loss of VSMC contractile phenotype. This was corroborated in mouse model of CKD and in human VSMCs treated with CKD serum. Gain-of-function and loss-of-function in vitro studies demonstrated that LARP7 acted as an endogenous positive regulator of VSMC contractile phenotype through its interaction with P300. The LARP7-P300 interaction augmented P300 histone acetyltransferase activity and thereby enhanced H3K27 acetylation at contractile gene promoters. The CKD microenvironment impaired the LARP7-P300 interaction and reduced H3K27 acetylation at contractile gene promoters, facilitating VSMC transdifferentiation toward osteogenic and inflammatory phenotypes. Further in vivo studies demonstrated that restoration of LARP7 in CKD VSMCs reversed their phenotype switching, and thereby attenuated vascular calcification and atherosclerosis. Conclusions Our study identified a novel role for LARP7 in maintaining VSMC contractile phenotype and mitigating CKD-associated vascular pathologies.