HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 287/3/H1179    most recent 00725.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Ritchie, R. H. Articles by Dusting, G. J. Search for Related Content PubMed PubMed Citation Articles by Ritchie, R. H. Articles by Dusting, G. J.

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

¹Howard Florey Institute and ²Baker Heart Research Institute, Melbourne, Victoria 8008, Australia

Submitted 5 August 2003 ; accepted in final form 7 April 2004

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 (PGI₂), may act to prevent hypertrophy has not been explored. In the vasculature, activation by PGI₂ 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 µM) virtually abolished the increase in [³H]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 µM, 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.

prostacyclin; endothelin-1; protein synthesis; cardiac hypertrophy

This article has been cited by other articles:

				K. Sattler and B. Levkau Sphingosine-1-phosphate as a mediator of high-density lipoprotein effects in cardiovascular protection Cardiovasc Res, May 1, 2009; 82(2): 201 - 211. [Abstract] [Full Text] [PDF]

				K. Shinmura, K. Tamaki, T. Sato, H. Ishida, and R. Bolli Prostacyclin attenuates oxidative damage of myocytes by opening mitochondrial ATP-sensitive K+ channels via the EP3 receptor Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2093 - H2101. [Abstract] [Full Text] [PDF]