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 3

VSMC-specific Kif13b deletion does not affect intestinal morphology or lipid absorption.

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VSMC-specific Kif13b deletion does not affect intestinal morphology or l...
Eight-week-old male Kif13bfl/fl and Kif13bVSMCKO mice were injected with AAV8-PCSK9-D377Y for 2 weeks and then fed a WD (n = 7 per group) or CD (n = 6 per group) for 20 weeks. (A) Representative images of H&E staining of intestinal segments (duodenum, jejunum, ileum, colon) show no morphological differences between the 2 genotypes. Scale bars: 200 μm. (B) Oral lipid tolerance test. Mice were fasted for 4 hours, followed by oral gavage of olive oil (10 μL/g), and then plasma TG levels were measured at each subsequent time point. (C) Quantitative analyses of the AUC in B. Data are presented as the mean ± SEM and were analyzed by 2-way ANOVA with Tukey post hoc test (C).