Mechanisms of ANG II-induced mitogenic responses: Role of 12-lipoxygenase and biphasic MAP kinase

被引:55
|
作者
Wen, YS
Nadler, JL
Gonzales, N
Scott, S
Clauser, E
Natarajan, R
机构
[1] CITY HOPE NATL MED CTR, DEPT DIABET ENDOCRINOL & METAB, DUARTE, CA 91010 USA
[2] COLL FRANCE, EXPT MED LAB, F-75005 PARIS, FRANCE
来源
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY | 1996年 / 271卷 / 04期
关键词
angiotensin II; 12-hydroxyeicosatetraenoic acid; mitogen-activated protein kinase; mitogenesis;
D O I
10.1152/ajpcell.1996.271.4.C1212
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The potential mechanisms of angiotensin II (ANG II)-induced mitogenesis were studied in a Chinese hamster ovary fibroblast cell line overexpressing the rat vascular type la ANG II receptor (CHO-AT(1a)). ANG II had potent mitogenic effects in these CHO-AT(1a) cells, leading to a sustained increase in cell number as well as a dose-dependent increase in DNA synthesis. ANG II treatment also induced a biphasic elevation of mitogen-activated protein (MAP) kinase activity of both p42(MAPK) and p44(MAPK) With a rapid early peak at 5 min (2- to B-fold) followed by a second sustained increase that reached a peak at 3 h (1.5- to S-fold). We have previously shown that the 12-lipoxygenase (12-LO) pathway of arachidonate metabolism plays a key role in ANG II-induced growth of vascular smooth muscle and adrenal cells. In the present study, ANG II (10(-7) M) increased the formation of the 12-LO product, 12-hydroxyeicosatetraenoic acid (12-HETE). ANG II-induced DNA synthesis was inhibited by a specific LO inhibitor, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (CDC, 10 mu M). In contrast, a cyclooxygenase blocker of arachidonate metabolism such as ibuprofen had no effect on ANG II-induced DNA synthesis. ANG II-induced DNA synthesis was also partially (32%) blocked by pertussis toxin (PTX). CDC and PTX also selectively blocked only the late (3 h) peak of ANG II-induced MAP kinase activity, suggesting that the late sustained peak of MAP kinase activity may be linked to the mitogenic effect of ANG II. Direct addition of 12-HETE (10(-7) M) led to a sustained increase in cell number similar to the effect of ANG II. 12-HETE also caused an increase in MAP kinase activity, and 12-HETE effects were blocked by PTX. These results suggest that ANG II-induced mitogenic response is associated with sustained MAP kinase activation and that LO activation may play a key role in this process.
引用
收藏
页码:C1212 / C1220
页数:9
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