Previously we found that interleukin-1β (IL-1β)-activated inducible nitric oxide (NO) synthase (iNOS) expression and that NO production can trigger cardiac fibroblast (CFb) apoptosis. Here, we provide evidence that angiotensin II (ANG II) significantly attenuated IL-1β-induced iNOS expression and NO production in CFbs while simultaneously decreasing apoptotic frequency. The anti-apoptotic effect of ANG II was abolished when cells were pretreated with the specific ANG II type 1 receptor (AT1) antagonist losartan, but not by the AT2 antagonist DP-123319. Furthermore, ANG II also protected CFbs from apoptosis induced by the NO donor diethylenetriamine NONOate and this effect was associated with phosphorylation of Akt/protein kinase B at Ser473. The effects of ANG II on Akt phosphorylation and NO donor-induced CFb apoptosis were abrogated when cells were preincubated with the specific phosphatidylinositol 3-kinase inhibitors wortmannin or LY-294002. These data demonstrate that ANG II protection of CFbs from IL-1β-induced apoptosis is associated with downregulation of iNOS expression and requires an intact phosphatidylinositol 3-kinase-Akt survival signal pathway. The findings suggest that ANG II and NO may play a role in regulating the cell population size by their countervailing influences on cardiac fibroblast viability.
In vitro
and in vivo
effects of UP 269-6, a new potent orally active nonpeptide angiotensin II receptor antagonist, on vascular smooth muscle cell proliferation
