Sanada Sumihiro, Taniyama Yoshiaki, Azuma Junya, Yuka Ikeda-Iwabe, Iwabayashi Masaaki, Rakugi Hiroma, Morishita Ryuichi
J Stem Cells. 2014;9(2):117-25.
Senescence of cells is associated with shortened or damaged telomeres and is characterized by permanent exit from the cell cycle and altered function. Cellular senescence is caused by repeated cell division, and also conditions of stress including inflammation and reactive oxygen species can lead to the development of premature senescence. At the cellular level, proliferative and oxidative-stress induced cell senescence related to a pro-inflammatory state might strongly contribute to age-associated impaired tissue and organ functions. Vascular cells (endothelial cells, vascular smooth muscle cells) and bone marrow-derived endothelial progenitor cells have been repeatedly shown to have pivotal role in the maintenance and regeneration of cardiovascular tissue. Therefore, the molecular mechanisms of vascular cell senescence have been extensively studied. However, therapeutic approaches to prevent cellular senescence in cardiovascular disease (CVD) are still limited. Hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF) are all potent angiogenic growth factors in animal models of ischemia, but their therapeutic effects are not the same in animal experiments and clinical trials. A multicenter, double-blind, placebo-controlled phase III clinical trial in Japan and a US phase II clinical trial of HGF gene therapy for critical limb ischemia (CLI) demonstrated a significant improvement in primary end points and an increase in transcutaneous partial pressure of oxygen even after one year compared with placebo, whereas effectiveness of VEGF and FGF treatment for CLI has not yet been shown. Moreover, our recent publication and another researcher demonstrated that HGF acts as an anti-inflammatory cytokine, while VEGF and FGF act as pro-inflammatory cytokine. This review overviews the outcomes of clinical trials using angiogenic growth factors, which have shown a dramatic effect in several animal studies. Additionally, interventions with HGF aimed at improving the regenerative capacity of stem/progenitor cells and vascular cells by preventing cellular senescence are discussed.
细胞衰老与端粒缩短或受损有关，其特征是永久性退出细胞周期并功能改变。细胞衰老由细胞反复分裂引起，炎症和活性氧等应激条件也可导致早衰的发生。在细胞水平上，增殖和氧化应激诱导的与促炎状态相关的细胞衰老可能在很大程度上导致与年龄相关的组织和器官功能受损。血管细胞（内皮细胞、血管平滑肌细胞）和骨髓来源的内皮祖细胞反复被证明在心血管组织的维持和再生中起关键作用。因此，血管细胞衰老的分子机制已得到广泛研究。然而，预防心血管疾病（CVD）中细胞衰老的治疗方法仍然有限。肝细胞生长因子（HGF）、血管内皮生长因子（VEGF）和成纤维细胞生长因子（FGF）在缺血动物模型中都是有效的促血管生成生长因子，但它们在动物实验和临床试验中的治疗效果并不相同。在日本进行的一项多中心、双盲、安慰剂对照的III期临床试验以及美国一项针对严重肢体缺血（CLI）的HGF基因治疗的II期临床试验表明，与安慰剂相比，主要终点有显著改善，甚至在一年后经皮氧分压也有所增加，而VEGF和FGF治疗CLI的有效性尚未得到证实。此外，我们最近的出版物以及另一位研究人员表明，HGF作为一种抗炎细胞因子发挥作用，而VEGF和FGF作为促炎细胞因子发挥作用。本综述概述了使用促血管生成生长因子的临床试验结果，这些结果在一些动物研究中显示出显著效果。此外，还讨论了旨在通过预防细胞衰老来提高干细胞/祖细胞和血管细胞再生能力的HGF干预措施。
