| First Author | Meganathan I | Year | 2025 |
| Journal | Atherosclerosis | Volume | 411 |
| Pages | 120567 | PubMed ID | 41202739 |
| Mgi Jnum | J:374874 | Mgi Id | MGI:8262508 |
| Doi | 10.1016/j.atherosclerosis.2025.120567 | Citation | Meganathan I, et al. (2025) Loss of ADAM17 in smooth muscle cells enhances their transformation to macrophage-like cells leading to more severe atherosclerosis in mice. Atherosclerosis 411:120567 |
| abstractText | BACKGROUND & AIMS: Atherosclerosis is a multicellular disease, and smooth muscle cells (SMCs) can contribute to plaque formation. ADAM17 (a distintegrin and metalloproteinase-17) is a membrane-bound proteinase that is upregulated in vascular disease and can regulate SMC functions. We investigated the role of ADAM17 in SMCs in atherosclerosis. METHODS & RESULTS: Human coronary plaques showed a high number of macrophage-like SMCs and ADAM17 expression. Male and female mice with inducible ADAM17 knockdown in SMCs (Ldlr(-/-)/Adam17(f/f)/Myh11-Cre(ERT2); Ldlr(-/-)/Adam17(SMC-KD)), ADAM17-intact (Ldlr(-/-)/Adam17(f/f); Ldlr(-/-)), and genetic control (Ldlr(-/-)/Myh11-Cre(ERT2)) received Western diet (HCD) or regular chow. Ldlr(-/-)/Adam17(SMC-KD)-HCD mice developed significantly more plaques, higher aortic cholesterol content, and aortic valve plaque and stiffness compared to Ldlr(-/-)-HCD mice, despite a comparable plasma lipid profile. SnRNAseq revealed a marked shift in SMC phenotypes from contractile to macrophage-like forms, and a greater population of proliferating inflammatory macrophages in Ldlr(-/-)/Adam17(SMC-KD)-HCD compared to Ldlr(-/-)-HCD aortas. The plaques in Ldlr(-/-)/Adam17(SMC-KD) mice showed a higher number of macrophage-like SMCs, decreased expression of SMC proteins (calponin, alpha-SMA, SM22alpha) and increased SMC atherogenic marker (galectin-3). In vitro, under atherogenic conditions, Adam17(KD) SMCs showed higher lipid content, increased lipid uptake and reduced efflux, associated with increased lipid uptake transporters (CD36, SRA1), and decreased efflux transporter, ABCA1, compared to control SMCs. In Ldlr(-/-)/Adam17(SMC-KD)-HCD aortas, membrane TNFR1 was stabilized, while the suppressed Ikkss-NFkappaB-LXRalpha pathway could underlie the decrease in ABCA1 expression. CONCLUSION: ADAM17 is a novel regulator of SMC function in atherosclerosis. Its loss increases lipid content in SMCs, transformation into synthetic and macrophage-like states, and worsened atherosclerosis. |
