Kanglexin counters vascular smooth muscle cell dedifferentiation and associated arteriosclerosis through inhibiting PDGFR

Shuang Yang; Yixiu Zhao; Shifeng Cao; Xinxin Liu; Min Feng; Yi Chen; Chunyue Ma; Tingting Zhan; Qi Zhang; Honglin Jia; Yu Zhao; Ming Tong; Yuanyuan Yu; Xue Liu; Baofeng Yang; Yan Zhang

doi:10.1016/j.phymed.2024.155704

Kanglexin counters vascular smooth muscle cell dedifferentiation and associated arteriosclerosis through inhibiting PDGFR

Phytomedicine. 2024 May 1:130:155704. doi: 10.1016/j.phymed.2024.155704. Online ahead of print.

Authors

Shuang Yang¹, Yixiu Zhao¹, Shifeng Cao¹, Xinxin Liu¹, Min Feng¹, Yi Chen¹, Chunyue Ma¹, Tingting Zhan¹, Qi Zhang¹, Honglin Jia¹, Yu Zhao¹, Ming Tong¹, Yuanyuan Yu¹, Xue Liu¹, Baofeng Yang², Yan Zhang³

Affiliations

¹ State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Labratoray -Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China.
² State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Labratoray -Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China. Electronic address: yangbf@ems.hrbmu.edu.cn.
³ State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Labratoray -Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China. Electronic address: zhangyan@ems.hrbmu.edu.cn.

PMID: 38759316
DOI: 10.1016/j.phymed.2024.155704

Abstract

Background: Dysregulation of vascular smooth muscle cell (VSMC) function leads to a variety of diseases such as atherosclerosis and hyperplasia after injury. However, antiproliferative drug targeting VSMC exhibits poor specificity. Therefore, there is an urgent to develop highly specific antiproliferative drugs to prevention and treatment VSMC dedifferentiation associated arteriosclerosis. Kanglexin (KLX), a new anthraquinone compound designed by our team, has potential to regulate VSMC phenotype according to the physicochemical properties.

Purpose: This project aims to evaluate the therapeutic role of KLX in VSMC dedifferentiation and atherosclerosis, neointimal formation and illustrates the underlying molecular mechanism.

Methods: In vivo, the ApoE^-/- mice were fed with high-fat diet (HFD) for a duration of 13 weeks to establish the atherosclerotic model. And rat carotid artery injury model was performed to establish the neointimal formation model. In vitro, PDGF-BB was used to induce VSMC dedifferentiation.

Results: We found that KLX ameliorated the atherosclerotic progression including atherosclerotic lesion formation, lipid deposition and collagen deposition in aorta and aortic sinus in atherosclerotic mouse model. In addition, The administration of KLX effectively ameliorated neointimal formation in the carotid artery following balloon injury in SD rats. The findings derived from molecular docking and surface plasmon resonance (SPR) experiments unequivocally demonstrate that KLX had potential to bind PDGFR-β. Mechanism research work proved that KLX prevented VSMC proliferation, migration and dedifferentiation via activating the PDGFR-β-MEK -ERK-ELK-1/KLF4 signaling pathway.

Conclusion: Collectively, we demonstrated that KLX effectively attenuated the progression of atherosclerosis in ApoE-/- mice and carotid arterial neointimal formation in SD rats by inhibiting VSMC phenotypic conversion via PDGFR-β-MEK-ERK-ELK-1/KLF4 signaling. KLX exhibits promising potential as a viable therapeutic agent for the treatment of VSMC phenotype conversion associated arteriosclerosis.

Keywords: Atherosclerosis; Neointimal hyperplasia; PDGFR-β; Phenotypic switching; VSMC.