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(Circulation. 2005;112:84-92.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

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; 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.

Correspondence to Fumitaka Ushikubi, MD, Department of Pharmacology, Asahikawa Medical College, Midorigaoka-Higashi 2-1-1-1, Asahikawa 078-8510, Japan. E-mail ushikubi{at}asahikawa-med.ac.jp

Received June 28, 2004; de novo received December 1, 2004; revision received February 28, 2005; accepted March 9, 2005.

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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