Loss of ADAM17 in smooth muscle cells enhances their transformation to macrophage-like cells leading to more severe atherosclerosis in mice

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 -CreERT2; Ldlr −/−/ Adam17 SMC−KD), ADAM17-intact ( Ldlr −/−/ Adam17 f/f; Ldlr −/−), and genetic control ( Ldlr −/−/ Myh11 -CreERT2) 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, α-SMA, SM22α) 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-NFκB-LXRα 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.