Inhibitory effects of interferon-gamma on myocardial hypertrophy.
Prostaglandin F(2alpha) (PGF(2alpha)) plays an important role in pathologic cardiac growth. After testing several immune cytokines, we found that interferon-gamma (IFN-gamma) inhibited responsiveness of adult myocytes to PGF(2alpha). The present study was designed to test the hypothesis that IFN-gamma inhibits cardiac hypertrophy induced by PGF(2alpha). Incubation of cultured adult rat cardiac myocytes with PGF(2alpha) caused cell spreading, which was inhibited by IFN-gamma. The inhibitory effect was not affected by nitric oxide (NO) synthase inhibitors. In addition, administration of fluprostenol, a more selective agonist at the PGF(2alpha) receptor, induced cardiac hypertrophy in rats. Chronic treatment with IFN-gamma inhibited this myocardial growth, and the inhibitory effect of IFN-gamma was not accompanied by an increase in myocardial NO synthase gene expression. Further, abdominal aortic constriction resulted in a substantial increase in heart, ventricular and left ventricular weights to BW ratio that was significantly attenuated by treatment with IFN-gamma. The results demonstrate that IFN-gamma inhibits the in vitro and in vivo effects of PGF(2alpha) on cardiac hypertrophy, and that the mechanism of action is likely independent of NO production. IFN-gamma also attenuated cardiac hypertrophy induced by pressure overload, suggesting that PGF(2alpha) plays a role in the pathogeneses of this severe type of cardiac hypertrophy.
Jin
Hongkui
H
Genentech, Incorporation, CA 94080, USA. hkj@gene.com
Li
Wei
W
Yang
Renhui
R
Ogasawara
Annie
A
Lu
Hsienwie
H
Paoni
Nicholas F
NF
D000818:Animals; D015152:Blotting, Northern; D006332:Cardiomegaly / Q000139:chemically induced / Q000188:drug therapy*; D015237:Dinoprost / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D006439:Hemodynamics; D006973:Hypertension / Q000188:drug therapy*; D007371:Interferon-gamma / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects*; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D012333:RNA, Messenger; D009569:Nitric Oxide; D007371:Interferon-gamma; D015237:Dinoprost; D019001:Nitric Oxide Synthase