Angiotensin II modulates nitric oxide-induced cardiac fibroblast apoptosis by activation of AKT/PKB.
Previously we found that interleukin-1beta (IL-1beta)-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-1beta-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-1beta-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.
Tian
Bin
B
Cardiovascular Division, Department of Medicine, University of Minnesota School of Medicine, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
Liu
Jian
J
Bitterman
Peter
P
Bache
Robert J
RJ
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D007375:Interleukin-1 / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009603:Nitroso Compounds / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000804:Angiotensin II; D007375:Interleukin-1; D019808:Losartan; D009569:Nitric Oxide; D020030:Nitric Oxide Donors; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D009603:Nitroso Compounds; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014662:Vasoconstrictor Agents; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; C496318:Nos2 protein, rat; C494920:Akt1 protein, rat