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.
OBJECTIVE: 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.
CONCLUSIONS: 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.
OBJECTIVE: 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.
CONCLUSIONS: 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.
摘要：
背景：血管平滑肌细胞（VSMC）功能失调导致多种疾病，如动脉粥样硬化和损伤后增生。然而,靶向VSMC的抗增殖药物表现出较差的特异性。因此,迫切需要开发高度特异性的抗增殖药物来预防和治疗VSMC去分化相关的动脉硬化。康乐欣（KLX），我们团队设计的一种新的蒽醌化合物，具有根据理化性质调节VSMC表型的潜力。
目的：该项目旨在评估KLX在VSMC去分化和动脉粥样硬化中的治疗作用，新内膜形成并说明了潜在的分子机制。
方法：体内，用高脂饮食(HFD)喂养ApoE-/-小鼠,持续13周,建立动脉粥样硬化模型.采用大鼠颈动脉损伤模型建立新生内膜形成模型。体外，PDGF-BB用于诱导VSMC去分化。
结果：我们发现KLX改善了动脉粥样硬化的进展，包括动脉粥样硬化病变的形成，动脉粥样硬化小鼠模型主动脉和主动脉窦中的脂质沉积和胶原沉积。此外,KLX的给药有效地改善了SD大鼠球囊损伤后颈动脉中的新内膜形成。来自分子对接和表面等离子体共振（SPR）实验的发现明确表明，KLX具有结合PDGFR-β的潜力。研究工作证明,KLX阻止VSMC增殖,通过激活PDGFR-β-MEK-ERK-ELK-1/KLF4信号通路进行迁移和去分化。
结论：总的来说，我们证明，KLX通过抑制PDGFR-β-MEK-ERK-ELK-1/KLF4信号传导的VSMC表型转化，有效地减弱了ApoE-/-小鼠动脉粥样硬化的进展和SD大鼠颈动脉新内膜的形成。KLX显示出作为治疗VSMC表型转化相关动脉硬化的可行治疗剂的有希望的潜力。
目的：该项目旨在评估KLX在VSMC去分化和动脉粥样硬化中的治疗作用，新内膜形成并说明了潜在的分子机制。
方法：体内，用高脂饮食(HFD)喂养ApoE-/-小鼠,持续13周,建立动脉粥样硬化模型.采用大鼠颈动脉损伤模型建立新生内膜形成模型。体外，PDGF-BB用于诱导VSMC去分化。
结果：我们发现KLX改善了动脉粥样硬化的进展，包括动脉粥样硬化病变的形成，动脉粥样硬化小鼠模型主动脉和主动脉窦中的脂质沉积和胶原沉积。此外,KLX的给药有效地改善了SD大鼠球囊损伤后颈动脉中的新内膜形成。来自分子对接和表面等离子体共振（SPR）实验的发现明确表明，KLX具有结合PDGFR-β的潜力。研究工作证明,KLX阻止VSMC增殖,通过激活PDGFR-β-MEK-ERK-ELK-1/KLF4信号通路进行迁移和去分化。
结论：总的来说，我们证明，KLX通过抑制PDGFR-β-MEK-ERK-ELK-1/KLF4信号传导的VSMC表型转化，有效地减弱了ApoE-/-小鼠动脉粥样硬化的进展和SD大鼠颈动脉新内膜的形成。KLX显示出作为治疗VSMC表型转化相关动脉硬化的可行治疗剂的有希望的潜力。
