Department of Cardiology, Bishan District People's Hospital in Chongqing Municipality, Chongqing 402760, China.
Department of Cardiology, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, China.
Oxid Med Cell Longev. 2021 Apr 21;2021:6625517. doi: 10.1155/2021/6625517. eCollection 2021.
The phenotypic transformation of proliferation and migration in vascular smooth muscle cells (VSMCs) from media to intima is the basic pathology of neointimal hyperplasia after angioplasty in hypertensive patients. Angiotensin II (AngII) stimulates oxidative stress in VSMC, inducing VSMC proliferation and migration, which is a critical factor in both developments of hypertension and angioplasty-induced arterial restenosis. Fisetin, a plant flavonoid polyphenol, has been reported to be antioxidative and potent senolytic. It is unknown whether fisetin would inhibit neointimal hyperplasia. Therefore, we investigated the role of fisetin in neointimal formation in vitro and in vivo. The rat thoracic aortic smooth muscle cells (A10 cells) stimulated by AngII were used as the in vitro neointimal hyperplasia model, where AngII significantly induced the proliferation and migration in A10 cells. We found that fisetin could dose-dependently inhibit the effect of AngII via inducing the expression of an antioxidant, paraoxonase-2 (PON2), whose overexpression could inhibit the proliferation and migration of A10 cells and downexpression by siRNA had the opposite effect. Furthermore, we found the mechanism of fisetin's inducing PON2 expression involved PPAR. Rosiglitazone, a PPAR agonist, could increase PON2 expression in A10 cells, while the PPAR inhibitor prevented the effect of fisetin on PON2. The in vivo neointimal hyperplasia model was established 2 weeks after the carotid artery balloon injury in SHR rats. Administration of fisetin (ip 3 mg/kg daily for 2 weeks) right after the injury significantly increased PON2 expression in the artery, inhibiting ROS production, and efficiently reduced carotid neointimal hyperplasia. These results indicate that fisetin increases the expression of antioxidant PON2 via activation of PPAR, reducing oxidative stress, inhibiting VSMC proliferation and migration, and alleviates neointimal hyperplasia after intimal injury. PON2 may be a potential therapeutic target to reduce arterial remodeling after angioplasty in hypertensive patients.
血管平滑肌细胞（VSMCs）从中膜向内膜迁移增殖的表型转化是高血压患者血管成形术后新生内膜增生的基本病理。血管紧张素 II（AngII）刺激 VSMC 氧化应激，诱导 VSMC 增殖和迁移，这是高血压和血管成形术后动脉再狭窄发展的关键因素。漆黄素是一种植物类黄酮多酚，具有抗氧化和强效衰老细胞溶解作用。目前尚不清楚漆黄素是否会抑制新生内膜增生。因此，我们研究了漆黄素在体外和体内抑制新生内膜形成的作用。用 AngII 刺激的大鼠胸主动脉平滑肌细胞（A10 细胞）作为体外新生内膜增生模型，结果发现 AngII 显著诱导 A10 细胞增殖和迁移。我们发现，漆黄素可通过诱导抗氧化酶对氧磷酶 2（PON2）的表达，从而剂量依赖性地抑制 AngII 的作用，PON2 的过表达可抑制 A10 细胞的增殖和迁移，而 siRNA 下调则产生相反的效果。此外，我们发现漆黄素诱导 PON2 表达的机制涉及 PPAR。PPAR 激动剂罗格列酮可增加 A10 细胞中 PON2 的表达，而 PPAR 抑制剂则可阻止漆黄素对 PON2 的作用。在 SHR 大鼠颈动脉球囊损伤后 2 周建立体内新生内膜增生模型。损伤后立即给予漆黄素（ip 3mg/kg，每日 1 次，共 2 周）可显著增加动脉中 PON2 的表达，抑制 ROS 产生，并有效减少颈动脉新生内膜增生。这些结果表明，漆黄素通过激活 PPAR 增加抗氧化酶 PON2 的表达，减少氧化应激，抑制 VSMC 增殖和迁移，减轻内膜损伤后的新生内膜增生。PON2 可能是降低高血压患者血管成形术后动脉重塑的潜在治疗靶点。
