Published Online
on June 27, 2005

A more recent version of this article appeared on July 5, 2005

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Submitted on June 28, 2004
Revised on February 28, 2005
Accepted on March 9, 2005

Augmented Cardiac Hypertrophy in Response to Pressure Overload in Mice Lacking the Prostaglandin I₂ Receptor

Akiyoshi Hara PhD, Koh-ichi Yuhki PhD, Takayuki Fujino MD, Takehiro Yamada PhD, Koji Takayama MD, Shuhko Kuriyama MD, Osamu Takahata MD, Hideji Karibe PhD, Yuji Okada MD, Chun-Yang Xiao PhD, Hong Ma MD, Shuh Narumiya MD, and Fumitaka Ushikubi MD^*

From the Department of Pharmacology, Asahikawa Medical College, Asahikawa (A.H., K.Y., T.F., T.Y., K.T., S.K., O.T., H.K., Y.O., C.-Y.X., H.M., F.U.), and the Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto (S.N.), Japan.

^* To whom correspondence should be addressed. E-mail: ushikubi{at}asahikawa-med.ac.jp.

Background--In the heart, the expressions of several types of prostanoid receptors have been reported. However, their roles in cardiac hypertrophy in vivo remain unknown. We intended to clarify the roles of these receptors in pressure overload-induced cardiac hypertrophy using mice lacking each of their receptors.

Methods and Results--We used a model of pressure overload-induced cardiac hypertrophy produced by banding of the transverse aorta in female mice. In wild-type mice subjected to the banding, cardiac hypertrophy developed during the observation period of 8 weeks. In mice lacking the prostaglandin (PG) I₂ receptor (IP^-/-), however, cardiac hypertrophy and cardiomyocyte hypertrophy were significantly greater than in wild-type mice at 2 and 4 weeks but not at 8 weeks, whereas there was no such augmentation in mice lacking the prostanoid receptors other than IP. In addition, cardiac fibrosis observed in wild-type hearts was augmented in IP^-/- hearts, which persisted for up to 8 weeks. In IP^-/- hearts, the expression level of mRNA for atrial natriuretic peptide, a representative marker of cardiac hypertrophy, was significantly higher than in wild-type hearts. In vitro, cicaprost, an IP agonist, reduced platelet-derived growth factor-induced proliferation of wild-type noncardiomyocytes, although it could not inhibit cardiotrophin-1-induced hypertrophy of cardiomyocytes. Accordingly, cicaprost increased cAMP concentration efficiently in noncardiomyocytes.

Conclusions--IP plays a suppressive role in the development of pressure overload-induced cardiac hypertrophy via the inhibition of both cardiomyocyte hypertrophy and cardiac fibrosis. Both effects have been suggested as originating from the action on noncardiomyocytes rather than cardiomyocytes.

Key words: hypertrophy • myocardium • pressure • prostaglandins • thromboxanes

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