期刊
ATHEROSCLEROSIS
卷 159, 期 2, 页码 269-279出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/S0021-9150(01)00505-6
关键词
angiotensin II; atherosclerosis; restenosis; serotonin; vascular smooth muscle cell
资金
- NHLBI NIH HHS [R01-HL50653, R01-HL39916] Funding Source: Medline
Vascular smooth muscle cell (VSMC) proliferation is a key feature in the development of atherosclerosis and restenosis after angioplasty, which can occur in response to many different humoral and mechanical stimuli. We investigated the growth promoting activities of two potent vasoactive substances, an-iotensin II (Ang II) and serotonin (5-HT), on cultured rabbit VSMCs. Growth-arrested VSMCs were incubated with serum-free medium containing different concentrations of Ang II in the presence or absence of 5-HT. [H-3]thymidine incorporation into VSMC DNA was measured as an index of cell proliferation. Ang II and 5-HT stimulated DNA synthesis in a dose-dependent manner with a maximal effect at 1.75 muM for Ang II (202%) and 50 muM for 5-HT (205%). When added together, low concentrations of Ang II (1 muM) and 5-HT (5 muM) synergistically induced DNA synthesis (363%). Candesartan (I muM), an AT(1) receptor antagonist, but not PD 123319 (1 muM), an AT(2) receptor antagonist, inhibited the mitogenic effect on Ang II and its interaction with 5-HT. Sarpogrelate (10 muM), a 5-HT2A receptor antagonist, and pertussis toxin (10 ng/ml) inhibited the mitogenic effect of 5-HT and its interaction with Ang II. The protein kinase C inhibitor Ro 31-8220 (0.1 muM), the Raf-1 inhibitor radicicol (10 muM), and the MAPK kinase inhibitor PD 098059 (10 muM) abolished mitogenic effects of Ang II and 5-HT, and also their synergistic interaction. The JAK2 inhibitor AG 490 (10 muM) had only a minimal inhibitory effect on Ang II-induced DNA synthesis but significantly inhibited the interaction of Ang II with 5-HT. The synergistic effect on Ang II (1 muM) with 5-HT (5 muM) on DNA synthesis was completely reversed by the combined use of both candesartan (I muM) and sarpogrelate (10 muM). Our results suggest that Ang II and 5-HT exert a synergistic interaction on VSMC proliferation via AT, and 5-HT2A receptors. The activation of MAPK and JAK/STAT pathways may explain the synergistic interaction between Ang II and 5-HT. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.
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