Allen Claire L, Bayraktutan Ulvi
Division of Stroke Medicine, Clinical Sciences Building, Nottingham City Hospital, University of Nottingham, Hucknall Road, Nottingham NG5 1PB, UK.
J Mol Cell Cardiol. 2008 Aug;45(2):198-208. doi: 10.1016/j.yjmcc.2008.05.021. Epub 2008 Jun 4.
Angiotensin II (Ang II) and platelet-derived growth factor-BB (PDGF-BB) are associated with excessive cell migration, proliferation and many growth-related diseases. However, whether these agents utilise similar mechanisms to trigger vascular pathologies remains to be explored. The effects of Ang II and PDGF-BB on coronary artery smooth muscle cell (CASMC) migration and proliferation were investigated via Dunn chemotaxis assay and the measurement of [(3)H]thymidine incorporation rates, respectively. Both atherogens produced similar degrees of cell migration which were dramatically inhibited by mevastatin (10 nM). However, the inhibitory effects of losartan (10 nM) and MnTBAP (a free radical scavenger; 50 microM) were found to be unique to Ang II-mediated chemotaxis. In contrast, MnTBAP, apocynin (an antioxidant and phagocytic NADPH oxidase inhibitor; 500 microM), mevastatin and pravastatin (100 nM) equally suppressed both Ang II and PDGF-BB-induced cellular growth. Although atherogens produced similar changes in NADPH oxidase, NOS and superoxide dismutase activities, they differentially regulated antioxidant glutathione peroxidase activity which was diminished by Ang II and unaffected by PDGF-BB. Studies with signal transduction pathway inhibitors revealed the involvement of multiple pathways i.e. protein kinase C, tyrosine kinase and MAPK in Ang II- and/or PDGF-BB-induced aforementioned enzyme activity changes. In conclusion, Ang II and PDGF-BB may induce coronary atherosclerotic disease formation by stimulating CASMC migration and proliferation through agent-specific regulation of oxidative status and utilisation of different signal transduction pathways.
血管紧张素II（Ang II）和血小板衍生生长因子-BB（PDGF-BB）与细胞过度迁移、增殖以及许多与生长相关的疾病有关。然而，这些因子是否利用相似机制引发血管病变仍有待探索。分别通过邓恩趋化性分析和[³H]胸苷掺入率测定，研究了Ang II和PDGF-BB对冠状动脉平滑肌细胞（CASMC）迁移和增殖的影响。两种致动脉粥样硬化因子均产生了相似程度的细胞迁移，而美伐他汀（10 nM）可显著抑制这种迁移。然而，发现氯沙坦（10 nM）和MnTBAP（一种自由基清除剂；50 μM）的抑制作用对于Ang II介导的趋化性是独特的。相反，MnTBAP、阿扑辛（一种抗氧化剂和吞噬性NADPH氧化酶抑制剂；500 μM）、美伐他汀和普伐他汀（100 nM）均同等程度地抑制了Ang II和PDGF-BB诱导的细胞生长。尽管致动脉粥样硬化因子在NADPH氧化酶、一氧化氮合酶和超氧化物歧化酶活性方面产生了相似的变化，但它们对抗氧化谷胱甘肽过氧化物酶活性的调节存在差异，该活性被Ang II降低而不受PDGF-BB影响。对信号转导通路抑制剂的研究揭示了多种通路的参与，即蛋白激酶C、酪氨酸激酶和丝裂原活化蛋白激酶参与了Ang II和/或PDGF-BB诱导的上述酶活性变化。总之，Ang II和PDGF-BB可能通过特异性调节氧化状态和利用不同信号转导通路刺激CASMC迁移和增殖，从而诱导冠状动脉粥样硬化疾病的形成。
