Genetic silencing of K3.1 inhibits atherosclerosis in ApoE null mice.

Increased expression of K3.1 has been found in vascular smooth muscle cells (SMC), macrophages, and T cells in atherosclerotic lesions from humans and mice. Pharmacological inhibition of K3.1 in limiting atherosclerosis has been demonstrated in mice and pigs, however direct, loss-of-function, i.e. gene silencing, studies are absent. Therefore, we generated K3.1Apoe (DKO) mice and assessed lesion development in the brachiocephalic artery (BCA) of DKO versus Apoe mice on a Western diet for 3 months. In BCAs of DKO mice, lesion size and relative stenosis were reduced by ~70% compared to Apoe mice, with no effect on medial or lumen area. Additionally, DKO mice exhibited a significant reduction in macrophage content within plaques compared to Apoe mice, independent of sex. migration assays showed a significant reduction in migration of bone marrow-derived macrophages (BMDMs) from DKO mice compared to those from Apoe mice. experiments using rat aortic smooth muscle cells revealed inhibition of PDGF-BB-induced MCP1/Ccl2 expression upon K3.1 inhibition, while activation of K3.1 further enhanced MCP1/Ccl2 expression. Both and analyses showed that silencing K3.1 had no significant effect on the collagen content of plaque. RNAseq analysis of BCA samples from DKO and Apoe mice revealed PPAR-dependent signaling as a potential key mediator of the reduction in atherosclerosis due to K3.1 silencing. Overall, this study provides the first genetic evidence that K3.1 is a critical regulator of atherosclerotic lesion development and composition and provides novel mechanistic insight into the link between K3.1 and atherosclerosis.