Vascular smooth muscle cell–derived KIF13B inhibits proinflammatory responses to protect against atherosclerosis
Guolin Miao, Yufei Han, Jingxuan Chen, Yiran Liu, Ge Zhang, Shaotong Pei, Yinqi Zhao, Yitong Xu, Liwen Zheng, Zhaoling Li, Xiangru Liu, Sijing Shi, Xuya Kang, Yahan Liu, Ling Zhang, Wei Huang, Yuhui Wang, Junnan Tang, Erdan Dong, Xunde Xian
Guolin Miao, Yufei Han, Jingxuan Chen, Yiran Liu, Ge Zhang, Shaotong Pei, Yinqi Zhao, Yitong Xu, Liwen Zheng, Zhaoling Li, Xiangru Liu, Sijing Shi, Xuya Kang, Yahan Liu, Ling Zhang, Wei Huang, Yuhui Wang, Junnan Tang, Erdan Dong, Xunde Xian
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Research Article Cardiology Vascular biology

Vascular smooth muscle cell–derived KIF13B inhibits proinflammatory responses to protect against atherosclerosis

Abstract

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of death worldwide, with plaque instability being a major culprit. Phenotypic switching of vascular smooth muscle cells (VSMCs) is a central event in atherosclerosis, driving both plaque progression and stability, yet the underlying mechanisms are incompletely understood, limiting drug development targeting this process. Kinesin family member 13B (KIF13B) has been implicated in vascular biology, but its function in VSMCs is unknown. Here, we demonstrate that VSMC-specific deletion of Kif13b in mice overexpressing proprotein convertase subtilisin/kexin type 9 (PCSK9) exacerbates lesion development and impairs plaque stability, characterized by thinner fibrous caps and increased inflammation. Mechanistically, we determined that KIF13B facilitated the ubiquitination and proteasomal degradation of Krüppel-like factor 4 (KLF4) through the potassium channel tetramerization domain–containing 10–dependent (KCTD10-dependent) pathway. This KIF13B/KCTD10 axis reduced KLF4 protein levels, thereby inhibiting the proinflammatory responses and fibroblast-like transition of VSMCs to preserve their contractile phenotype. Importantly, the adverse effects of Kif13b deficiency on atherogenesis were effectively rescued by the small-molecule KLF4 inhibitor Kenpaullone. Our results unveil a VSMC-specific atheroprotective role for KIF13B, define the KIF13B/KCTD10/KLF4 pathway as a key regulatory axis governing VSMC fate and plaque stability, and validate the therapeutic potential of KIF13B for treating advanced atherosclerosis.

Authors

Guolin Miao, Yufei Han, Jingxuan Chen, Yiran Liu, Ge Zhang, Shaotong Pei, Yinqi Zhao, Yitong Xu, Liwen Zheng, Zhaoling Li, Xiangru Liu, Sijing Shi, Xuya Kang, Yahan Liu, Ling Zhang, Wei Huang, Yuhui Wang, Junnan Tang, Erdan Dong, Xunde Xian

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Figure 7

KIF13B drives KLF4 degradation in atherosclerosis through KCTD10-mediated ubiquitination.

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KIF13B drives KLF4 degradation in atherosclerosis through KCTD10-mediate...
(A) Representative Western blots and quantitative analysis of KLF4 in HASMCs transfected with scramble or siKIF13B and treated with PBS or 10 μM MG132 in the presence of 50 μg/mL CHX for the indicated durations (n = 3 independent biological replicates). (B) Co-IP analysis and quantification of the ubiquitination of KLF4 (n = 3 independent biological replicates). (C) Venn diagram illustrates the intersection of commonly downregulated genes across DEGs in VSMCs from Ldlr–/– Kif13b–/– versus Ldlr–/– mice fed a WD for 12 weeks, DEGs from unstable versus stable atherosclerotic plaques (GSE120521), and E3 ligase. DEGs with an FDR of less than 0.05 and a log2 FC of less than 0 were included. (D) Left: Representative Western blots of KCTD10 and SKP1 protein expression in HASMCs transfected with scramble or siKIF13B and subsequently treated with oxLDL (50 μg/mL) for 48 hours (n = 3 independent biological replicates). Right: Representative Western blots of KCTD10 and SKP1 protein expression in HASMCs infected with LV expressing GFP-HA or KIF13B-HA and subsequently treated with oxLDL (50 μg/mL) for 48 hours (n = 3 independent biological replicates). (E) Quantitative analysis of KCTD10 and SKP1 protein expression shown in D. (F) Immunofluorescence staining and quantification of α-SMA and KCTD10 in the aortic root of Kif13bfl/fl and Kif13bVSMCKO mice injected with AAV8-PCSK9-D377Y and then fed a WD for 20 weeks (n = 8 per group). (G) Violin plots of KCTD10 mRNA expression in different cells in human atherosclerotic plaque tissues. (H) Immunofluorescence staining and quantification of α-SMA and KCTD10 expression in human carotid artery plaque tissues (n = 6 per group). White arrows indicate the content of KCTD10 in atherosclerotic plaque. Scale bars: 50 μm and 100 μm. Data are presented as the mean ± SEM and were analyzed by 2-way ANOVA with Tukey’s post hoc test (A), 2-tailed, unpaired Student’s t test (B, F, and H), or Wilcoxon rank-sum test (G).