Thymosin β4 preserves vascular smooth muscle phenotype in atherosclerosis via regulation of low density lipoprotein related protein 1 (LRP1)

Int Immunopharmacol. 2023 Feb;115:109702. doi: 10.1016/j.intimp.2023.109702. Epub 2023 Jan 20.ABSTRACTAtherosclerosis is a progressive, degenerative vascular disease and a leading cause of morbidity and mortality. In response to endothelial damage, platelet derived growth factor (PDGF)-BB induced phenotypic modulation of medial smooth muscle cells (VSMCs) promotes atherosclerotic lesion formation and destabilisation of the vessel wall. VSMC sensitivity to PDGF-BB is determined by endocytosis of Low density lipoprotein receptor related protein 1 (LRP1)-PDGFR β complexes to balance receptor recycling with lysosomal degradation. Consequently, LRP1 is implicated in various arterial diseases. Having identified Tβ4 as a regulator of LRP1-mediated endocytosis to protect against aortic aneurysm, we sought to determine whether Tβ4 may additionally function to protect against atherosclerosis, by regulating LRP1-mediated growth factor signalling. By single cell transcriptomic analysis, Tmsb4x, encoding Tβ4, strongly correlated with contractile gene expression and was significantly down-regulated in cells that adopted a modulated phenotype in atherosclerosis. We assessed susceptibility to atherosclerosis of global Tβ4 knockout mice using the ApoE-/- hypercholesterolaemia model. Inflammation, elastin integrity, VSMC phenotype and signalling were analysed in the aortic root and descending aorta. Tβ4KO; ApoE-/- mice develop larger atherosclerotic plaques than control mice, with medial...
Source: International Immunopharmacology - Category: Allergy & Immunology Authors: Source Type: research