Kyaw M, Yoshizumi M, Tsuchiya K, Kirima K, Tamaki T
Department of Pharmacology, The University of Tokushima School of Medicine, Japan.
Hypertens Res. 2001 May;24(3):251-61. doi: 10.1291/hypres.24.251.
Angiotensin II (Ang II) induces vascular smooth muscle cell (VSMC) hypertrophy, which results in several cardiovascular diseases. Ang II-induced cellular events have been mediated, in part, by reactive oxygen species (ROS) which also involve activation of mitogen-activated protein (MAP) kinases. Although it has been proposed that the therapeutic administration of antioxidants is useful for vascular diseases, the precise mechanisms which regulate ROS-sensitive signaling events have not been well characterized. Thus, we hypothesized that antioxidants may affect ROS-mediated MAP kinases activation induced by Ang II. The present findings showed that Ang II stimulated rapid and significant activation of ERK 1/2, JNK and p38 MAPK in cultured rat aortic smooth muscle cells (RASMC). Ang II-induced ERK 1/2 activation was not affected by all antioxidants examined, whereas JNK was sensitive to all antioxidants. In contrast, p38 MAPK activation was inhibited by DPI and ascorbic acid concentration-dependently, but by NAC only at high concentration. DETC and Trolox C had no effects on p38 MAPK activation by Ang II. We further examined the effects of antioxidants on Ang II-induced increases in oxygen consumption as an index of ROS generation in RASMC. DPI strongly inhibited Ang II-induced increases in oxygen consumption. DETC also inhibited Ang II-induced oxygen consumption, whereas ascorbic acid markedly augmented it. These findings suggest that the inhibitory effects of antioxidants on MAP kinases activation in VSMC are attributable, in part, to their modulating effects on ROS generation by Ang II in VSMC. Thus, inhibition of MAP kinases by antioxidants may imply their usefulness for relief of cardiovascular diseases.
血管紧张素II（Ang II）可诱导血管平滑肌细胞（VSMC）肥大，进而引发多种心血管疾病。Ang II诱导的细胞事件部分是由活性氧（ROS）介导的，ROS还参与丝裂原活化蛋白（MAP）激酶的激活。尽管有人提出抗氧化剂的治疗性应用对血管疾病有用，但调节ROS敏感信号事件的精确机制尚未得到充分阐明。因此，我们推测抗氧化剂可能会影响Ang II诱导的ROS介导的MAP激酶激活。目前的研究结果表明，Ang II可刺激培养的大鼠主动脉平滑肌细胞（RASMC）中ERK 1/2、JNK和p38 MAPK的快速且显著激活。Ang II诱导的ERK 1/2激活不受所检测的所有抗氧化剂的影响，而JNK对所有抗氧化剂均敏感。相反，p38 MAPK激活受到二苯基碘鎓（DPI）和抗坏血酸的浓度依赖性抑制，但仅在高浓度下受N-乙酰半胱氨酸（NAC）抑制。二乙三胺五乙酸（DETC）和生育三烯酚（Trolox C）对Ang II诱导的p38 MAPK激活没有影响。我们进一步研究了抗氧化剂对Ang II诱导的RASMC中氧消耗增加的影响，以此作为ROS生成的指标。DPI强烈抑制Ang II诱导的氧消耗增加。DETC也抑制Ang II诱导的氧消耗，而抗坏血酸则显著增强了氧消耗。这些发现表明，抗氧化剂对VSMC中MAP激酶激活的抑制作用部分归因于它们对VSMC中Ang II产生的ROS的调节作用。因此，抗氧化剂对MAP激酶的抑制作用可能意味着它们对缓解心血管疾病有用。
