Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
Division of Cardiology, Cheng-Hsin Rehabilitation Medical Centre, Taipei, Taiwan.
J Cardiovasc Transl Res. 2020 Apr;13(2):158-170. doi: 10.1007/s12265-019-09889-y. Epub 2019 Nov 7.
The enhanced activity of endothelial progenitor cells (EPCs) by AMP-activated protein kinase (AMPK) agonists might explain the reversal of chronic heart failure (CHF)-mediated endothelial dysfunction. We studied baseline circulating EPC numbers in patients with heart failure and clarified the effect of fenofibrate on both circulating angiogenic cell (CAC) and late EPC activity. The numbers of circulating EPCs in CHF patients were quantified by flow cytometry. Blood-derived mononuclear cells were cultured, and CAC and late EPC functions, including fibronectin adhesion, tube formation, and migration, were evaluated. We focused on the effect of fenofibrate, an AMPK agonist, on EPC function and Akt/eNOS cascade activation in vitro. The number of circulating EPCs (CD34/KDR) was significantly lower in CHF patients (ischemic cardiomyopathy (ICMP): 0.07%, dilated cardiomyopathy (DCMP): 0.068%; p < 0.05) than in healthy subjects (0.102% of the gating region). In CACs, fibronectin adhesion function was reversed by fenofibrate treatment (p < 0.05). Similar results were also found for tube formation and migration in late EPCs, which were significantly improved by fenofibrate in an AMPK-dependent manner (p < 0.05), suggesting that fenofibrate reversed CACs and late EPC dysfunction in CHF patients. The present findings reveal the potential application of the AMPK agonist fenofibrate to reverse endothelial dysfunction in CHF patients.
AMP 激活的蛋白激酶 (AMPK) 激动剂增强内皮祖细胞 (EPC) 的活性可能解释了慢性心力衰竭 (CHF) 介导的内皮功能障碍的逆转。我们研究了心力衰竭患者的基线循环 EPC 数量，并阐明了非诺贝特对循环血管生成细胞 (CAC) 和晚期 EPC 活性的影响。通过流式细胞术定量循环 EPC 数量。培养血液来源的单核细胞，并评估 CAC 和晚期 EPC 功能，包括纤维连接蛋白黏附、管形成和迁移。我们专注于 AMPK 激动剂非诺贝特对体外 EPC 功能和 Akt/eNOS 级联激活的影响。CHF 患者的循环 EPC 数量（CD34/KDR）明显低于健康受试者（缺血性心肌病 (ICMP)：0.07%，扩张型心肌病 (DCMP)：0.068%；p < 0.05）。在 CAC 中，非诺贝特处理逆转了纤维连接蛋白黏附功能（p < 0.05）。在晚期 EPC 中也发现了类似的管形成和迁移结果，非诺贝特以 AMPK 依赖的方式显著改善了这些结果（p < 0.05），这表明非诺贝特逆转了 CHF 患者的 CAC 和晚期 EPC 功能障碍。这些发现揭示了 AMPK 激动剂非诺贝特在逆转 CHF 患者内皮功能障碍方面的潜在应用。
