Activation of IP prostanoid receptors prevents cardiomyocyte hypertrophy via cAMP-dependent signaling

被引:26
作者
Ritchie, RH
Rosenkranz, AC
Huynh, LP
Stephenson, T
Kaye, DM
Dusting, GJ
机构
[1] Baker Heart Res Inst, Melbourne, Vic 8008, Australia
[2] Howard Florey Inst Expt Physiol & Med, Melbourne, Vic 8008, Australia
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 2004年 / 287卷 / 03期
关键词
prostacyclin; endothelin-1; protein synthesis; cardiac hypertrophy;
D O I
10.1152/ajpheart.00725.2003
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The antihypertrophic action of angiotensin-converting enzyme inhibitors in the heart results partly from local potentiation of bradykinin. We have demonstrated that the antihypertrophic action of bradykinin is mediated by the release of nitric oxide from endothelium and elevation of cardiomyocyte cGMP. Whether other paracrine factors derived from the coronary endothelium, such as prostacyclin (PGI(2)), may act to prevent hypertrophy has not been explored. In the vasculature, activation by PGI(2) of IP and EP1 prostanoid receptors elicits vasodilatation ( via cAMP-dependent signaling) and vasoconstriction, respectively. The present objective was to determine whether IP prostanoid receptor activation has antihypertrophic actions in adult rat cardiomyocytes (ARCM). The selective IP agonist cicaprost ( 1 muM) virtually abolished the increase in [H-3] phenylalanine incorporation ( a marker of hypertrophy) induced either by endothelin-1 (ET-1; 60 nM, n = 10, P < 0.005) or by angiotensin II (1 μM, n = 6, P < 0.005). Cicaprost also inhibited ET-1 induction of c-fos mRNA expression, an additional marker of hypertrophy in ARCM (n = 5, P < 0.005). In the absence of hypertrophic stimuli, cicaprost alone did not significantly influence either marker. The antihypertrophic actions of cicaprost were mimicked by the dual IP/EP1 agonist iloprost (1 μM) in the presence of the EP1 antagonist AH-6809 (3 μM). Furthermore, cicaprost modestly but significantly increased cardiomyocyte cAMP content by 13 +/- 6% ( P < 0.05, n = 4), and the antihypertrophic effect of cicaprost was lost in the presence of the cAMP-dependent protein kinase inhibitor H-89 ( 1 muM, n = 5, P < 0.05). However, ET-1 also induced increases in the activity of the intracellular growth signals ERK1 ( by 3-fold) and ERK2 ( by 5-fold) in ARCM, and these were not inhibited by cicaprost ( P < 0.01, n = 5). Activation of IP receptors thus represents a novel approach to prevention of hypertrophy, and this effect is linked to cAMP-dependent signaling.
引用
收藏
页码:H1179 / H1185
页数:7
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