VSMC-specific deletion of Kif13b exacerbated atherosclerosis and impaired plaque stability in mice, effects that were effectively rescued by the small-molecule KLF4 inhibitor Kenpaullone.
Does KIF13B expression in VSMCs or pharmacological inhibition of KLF4 with Kenpaullone improve atherosclerotic plaque stability and reduce lesion development?
KIF13B in vascular smooth muscle cells protects against atherosclerosis by promoting KLF4 degradation, and pharmacological inhibition of KLF4 with Kenpaullone stabilizes vulnerable plaques in preclinical models.
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 identified that KIF13B facilitates the ubiquitination and proteasomal degradation of Krüppel-like factor 4 (KLF4) through the Potassium channel tetramerization domain containing 10 (KCTD10)-dependent pathway. This KIF13B/KCTD10 axis reduces KLF4 protein levels, thereby inhibiting the pro-inflammatory 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 its therapeutic potential for treating advanced atherosclerosis.
Miao et al. (Thu,) conducted a other in Atherosclerosis. Kif13b deletion / Kenpaullone vs. Wild-type / Vehicle was evaluated on Atherosclerotic lesion development and plaque stability. VSMC-specific deletion of Kif13b exacerbated atherosclerosis and impaired plaque stability in mice, effects that were effectively rescued by the small-molecule KLF4 inhibitor Kenpaullone.