bioRxiv2024
RationaleNeointimal formation is the major cause of cardiovascular diseases such as atherosclerosis and restenosis. Although restenosis rates are significantly reduced by the development of drug-eluting, the stent may not be implanted at all atherosclerotic sites, and long-term dual anti-platelet therapy is needed after stent implantation. Thus, it is essential to elucidate the detailed mechanisms underlying neointimal formation for developing novel therapies. Latexin (LXN), a previously identified pro-inflammatory protein, is highly expressed in vasculature and its expression is regulated by shear stress. Whether it plays a role in vascular remodeling, however, remains unknown. ObjectiveTo determine whether LXN is involved in neointimal formation, and if so, to define the molecular mechanisms involved. Methods and ResultsWe found that the expression of LXN was significantly increased in neointimal hyperplasia, as determined by western blot. Immunofluorescent staining indicated that increased LXN expression was predominantly localized in smooth muscle cells and macrophages. To determine the cell specific roles of LXN in neointimal formation after injury, we generated global, smooth muscle cell (SMC)-specific, endothelial specific-, and myeloid-specific LXN knockout (KO) mice. We found that global, SMC-, and myeloid-specific LXN deficiency markedly prevented neointimal hyperplasia in mice after carotid artery ligation, whereas LXN deficiency in endothelial cells had no effects. Mechanistically, we found that LXN deficiency in SMCs significantly attenuated SMC proliferation and migration, mainly through inhibiting the expression of platelet-derived growth factor (PDGF) receptors. Intriguely, LXN deficiency in macrophages inhibited monocyte chemoattractant protein-1 (MCP-1)-induced macrophage migration through inhibiting ERK phosphorylation. ConclusionsIn summary, we for the first time demonstrated that LXN is essentially involved in SMC proliferation and microphage migration. Specific inhibition of LXN signaling may provide a novel therapeutic strategy for the treatment of cardiovascular diseases, such as restenosis and atherosclerosis. Novelty and SignificanceO_ST_ABSWhat is known?C_ST_ABSO_LILatexin (LXN) is considered to be a novel pro-inflammatory protein and its expression is responsive to laminar shear stress. C_LIO_LIVascular inflammation, SMC proliferation, and macrophage migration are critical events in neointimal hyperplasia. C_LI What new information does this article contribute?O_LILXN is elevated in carotid artery ligation-induced neointimal hyperplasia in mice. C_LIO_LISMC-specific LXN deficiency prevents neointimal hyperplasia through inhibiting SMC proliferation migration via attenuating platelet-derived growth factor receptor expression. C_LIO_LIMyeloid-specific LXN deficiency prevents neointimal hyperplasia through inhibiting monocyte chemoattractant protein-1-induced macrophage migration and extracellular signal-regulated kinase phosphorylation. C_LI Neointimal formation is the major cause of cardiovascular disease such as atherosclerosis and restenosis after stenting or balloon angioplasty. Because of the development of drug-eluting stents, restenosis rates have been significantly reduced; however, it is still essential to explore the detailed mechanisms underlying neointimal hyperplasia. Latexin (LXN) is considered a novel pro-inflammatory protein that is ubiquitously expressed in vascular and immune cells. We found that LXN is elevated in neointimal hyperplasia, and its deficiency in SMCs and macrophages, but not in ECs, markedly prevents neointimal formation after carotid artery ligation in mice. Mechanistically, LXN deficiency in SMCs prevents SMC proliferation and migration via attenuation of platelet-derived growth factor receptor expression. Further, myeloid-specific LXN deficiency inhibits monocyte chemoattractant protein-1-induced macrophage migration via attenuation of extracellular signal-regulated kinase phosphorylation. For the first time, the present study demonstrated that LXN is a crucial mediator implicated in SMC biology and macrophage migration.