Yang Jing, Li Jie, Wei Ting-Ting, Pang Ji-Yan, Du Yan-Hua
Department of Pharmacology, Cardiac & Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
Department of Anesthesiology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, China.
ACS Pharmacol Transl Sci. 2023 Oct 10;6(11):1673-1680. doi: 10.1021/acsptsci.3c00136. eCollection 2023 Nov 10.
Aging is associated with an increased risk of cardiovascular disease. Previous studies have demonstrated that compound 3 (C3), a derivative of marine compound xyloallenoide A isolated from the mangrove fungus sp. (no. 2508), exhibited strong angiogenic activities in zebrafish. In this study, we examined the effects of C3 on the senescence of endothelial progenitor cells isolated from human peripheral blood (hEPCs). The results showed that treatment with angiotensin II (AngII) for 24 h induced hEPC senescence, as demonstrated by increased SA-β-galactosidase staining. Moreover, there is a significant decrease in telomerase activity and cellular viability in AngII-treated hEPCs. These changes in aging hEPCs were greatly recovered by C3 in a dose-dependent manner. Furthermore, C3 significantly restored the AngII-induced decrease of sirtuin type 1 (SIRT1) expression, a well-known antiaging protein. In addition, AngII increased AMP-activated protein kinase (AMPK) phosphorylation and reduced Akt phosphorylation in aging hEPCs, which were also reversed by C3. Importantly, the inhibition of C3 on hEPC senescence and AMPK/Akt dysregulation was significantly attenuated by the SIRT1-specific inhibitor nicotinoyl. These results indicated that C3 protects hEPC against AngII-induced senescence by increasing SIRT1 expression levels and balancing the AMPK/Akt signaling pathway. The inhibition of hEPCs senescence by C3 might protect EPCs against dysfunction induced by pathological factors in the elderly population. C3 may provide a novel drug candidate for the treatment of aging-related disorders.
衰老与心血管疾病风险增加相关。先前的研究表明，化合物3（C3）是从红树林真菌sp.（编号2508）中分离出的海洋化合物木糖别联烯酸A的衍生物，在斑马鱼中表现出强大的血管生成活性。在本研究中，我们检测了C3对从人外周血分离的内皮祖细胞（hEPCs）衰老的影响。结果显示，用血管紧张素II（AngII）处理24小时可诱导hEPC衰老，这通过衰老相关β-半乳糖苷酶染色增加得以证明。此外，AngII处理的hEPC中端粒酶活性和细胞活力显著降低。衰老hEPCs的这些变化被C3以剂量依赖性方式显著恢复。此外，C3显著恢复了AngII诱导的沉默调节蛋白1（SIRT1）表达的降低，SIRT1是一种著名的抗衰老蛋白。另外，AngII增加了衰老hEPCs中AMP激活的蛋白激酶（AMPK）的磷酸化并降低了Akt的磷酸化，这些也被C3逆转。重要的是，SIRT1特异性抑制剂烟酰可显著减弱C3对hEPC衰老和AMPK/Akt失调的抑制作用。这些结果表明，C3通过增加SIRT1表达水平和平衡AMPK/Akt信号通路来保护hEPC免受AngII诱导的衰老。C3对hEPCs衰老的抑制作用可能保护EPCs免受老年人群病理因素诱导的功能障碍。C3可能为治疗与衰老相关的疾病提供一种新型药物候选物。
