Inhibition of CDK9 attenuates atherosclerosis by inhibiting inflammation and phenotypic switching of vascular smooth muscle cells.
Inhibition of CDK9 attenuates atherosclerosis by inhibiting inflammation and phenotypic switching of vascular smooth muscle cells.
复制标题
抑制 CDK9 可通过抑制血管平滑肌细胞的炎症和表型转换来减轻动脉粥样硬化
DOI：
10.18632/aging.202998
复制
发表时间：
2021-06-08
期刊：
影响因子：
--
通讯作者：
Liang G
中科院分区：
文献类型：
--
作者：
Huang S;Luo W;Wu G;Shen Q;Zhuang Z;Yang D;Qian J;Hu X;Cai Y;Chattipakorn N;Huang W;Liang G
背景：最近的研究表明血管平滑肌细胞（VSMC）功能障碍在动脉粥样硬化中发挥着关键作用。细胞周期蛋白依赖性激酶 9 (CDK9) 是动脉粥样硬化的潜在生物标志物，在冠状动脉疾病患者血清中显着增加，并在炎症性疾病中发挥重要作用。本研究旨在探讨 CDK9 抑制在减轻动脉粥样硬化中的药理学作用。方法：采用小分子 CDK9 抑制剂 LDC000067 治疗高脂饮食 (HFD) 喂养的 ApoE-/- 小鼠和人 VSMC。结果：结果显示，在HFD诱导的ApoE-/-小鼠动脉粥样硬化中观察到炎症和VSMC表型转换，并伴有血清中CDK9升高以及与VSMC共存的动脉粥样硬化病变。 LDC000067 治疗显着抑制 HFD 诱导的炎症、增殖和 VSMC 表型转换，从而减少 ApoE-/- 小鼠的动脉粥样硬化，但对血浆脂质没有影响。进一步的体外研究证实，LDC000067 和 siRNA 介导的 CDK9 敲低可通过抑制人 VSMC 中的 NF-κB 信号通路，逆转 ox-LDL 诱导的炎症和 VSMC 从收缩表型到合成表型的表型转换。结论：这些结果表明，抑制CDK9可能是预防动脉粥样硬化的新治疗靶点。
Background: Recent studies have demonstrated a key role of vascular smooth muscle cell (VSMC) dysfunction in atherosclerosis. Cyclin-dependent kinases 9 (CDK9), a potential biomarker of atherosclerosis, was significantly increased in coronary artery disease patient serum and played an important role in inflammatory diseases. This study was to explore the pharmacological role of CDK9 inhibition in attenuating atherosclerosis. Methods: A small-molecule CDK9 inhibitor, LDC000067, was utilized to treat the high fat diet (HFD)-fed ApoE-/- mice and human VSMCs. Results: The results showed that inflammation and phenotypic switching of VSMCs were observed in HFD-induced atherosclerosis in ApoE-/- mice, which were accompanied with increased CDK9 in the serum and atherosclerotic lesions where it colocalized with VSMCs. LDC000067 treatment significantly suppressed HFD-induced inflammation, proliferation and phenotypic switching of VSMCs, resulting in reduced atherosclerosis in the ApoE-/- mice, while had no effect on plasma lipids. Further in vitro studies confirmed that LDC000067 and siRNA-mediated CDK9 knockdown reversed ox-LDL-induced inflammation and phenotypic switching of VSMCs from a contractile phenotype to a synthetic phenotype via inhibiting NF-κB signaling pathway in human VSMCs. Conclusion: These results indicate that inhibition of CDK9 may be a novel therapeutic target for the prevention of atherosclerosis.