Colchicine reduces neointima formation and VSMC phenotype transition by modulating SRF-MYOCD activation and autophagy

• Published in: Acta pharmacologica Sinica 2024-12
• Main Authors: Zhang, Bu-Chun, Zhu, Wen-Ya, Wang, Sheng-Nan, Zhu, Meng-Meng, Ma, Hui, Dong, Liang, Yang, Xiao-Xiao, Ma, Chuan-Rui, Ma, Li-Kun, Chen, Yuan-Li
• Format: Article
• Language: English
• ISSN: 1745-7254; 1745-7254
• DOI: 10.1038/s41401-024-01438-x

Vascular smooth muscle cell (VSMC) phenotype transformation significantly contributes to vascular intimal hyperplasia. However, effective preventive and therapeutic measures are lacking. Colchicine, a binary alkaloid derived from Colchicum autumnale, is traditionally used for treating inflammatory diseases. Its role in neointima formation is not fully understood. Here, we investigated the role of colchicine in vascular intimal hyperplasia. We found that colchicine significantly reduced vascular intimal hyperplasia in an animal model at 7, 14, and 28 days post carotid artery ligation and increased the number of contractile-phenotype VSMCs (SMA-positive cells) in the neointimal areas. In vitro experiments demonstrated that colchicine facilitated the transition of VSMCs from a proliferative phenotype to a contractile phenotype. Additionally, colchicine attenuated PDGF-BB-induced phenotypic conversion and upregulated the expression of serum response factor (SRF) and myocardin (MYOCD). Further molecular mechanistic studies revealed that colchicine inhibited the expression of forkhead box protein O3A (FOXO3A) to increase the activation of the SRF‒MYOCD complex. FOXO3A can bind to MSX1/2, thereby inhibiting the expression of SRF-MYOCD and contractile genes. Moreover, colchicine maintains vascular homeostasis and stabilizes the contractile phenotype by affecting the expression of autophagy-related genes (LC3II, p62, and Beclin-1) induced by FOXO3A. Additionally, colchicine inhibited monocyte/macrophage infiltration and inflammatory cytokine expression. In summary, this study suggests that colchicine inhibits vascular intimal hyperplasia by modulating FOXO3A-mediated SRF-MYOCD activation and autophagy, providing new insights for future therapeutic approaches targeting occlusive vascular diseases.