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Expression of Urocortin and Corticotropin-Releasing Factor Receptor Subtypes in the Human Heart

Department of Pathology (Y.K., Y.M., C.K., A.D.D., T.S., H.S.), Department of Molecular Biology (K.Ta.), Second Department of Internal Medicine (K.To.), Tohoku University School of Medicine; and Department of Respiratory Oncology/Molecular Medicine (M.E., T.N.), Tohoku University Institute of Development, Aging and Cancer, Sendai, Japan 980-8575

Address all correspondence and requests for reprints to: Yuichiro Kimura, M.D., Department of Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. E-mail: kimuyu{at}patholo2.med.tohoku.ac.jp

Urocortin (Ucn) is a new member of the corticotropin-releasing factor (CRF) neuropeptide family and has positive inotropic actions and protective effects against ischemia in the rat heart. Ucn binds with very high affinity to both CRF receptor type 1 (CRF-R1) and CRF receptor type 2 (CRF-R2). However, to date, endogenous ligand(s) for CRF receptors expressed in the human heart have yet to be elucidated. In this study, we therefore examined the expression of Ucn and CRF receptors in human heart obtained at autopsy by RT-PCR, immunohistochemistry, and RIA. RT-PCR analysis demonstrated that Ucn and CRF-R2 mRNAs were detected in all four chambers. CRF-R1 mRNA was weakly present in some left atria, left ventricles, and in one right ventricle. CRF-R2ß mRNA was detected predominantly in the left atrium. CRF mRNA was not detected in any of the four chambers. Immunostaining for both Ucn and CRF receptors was detected in cardiac myocytes in all four chambers. Ucn-like immunoreactivity was detected in all four chambers by RIA, with the highest concentrations in the left ventricle (1.90 ± 0.5 pmol/g wet weight, mean ± SEM; n = 4). On the other hand, CRF-like immunoreactivity was very low or undetectable in the human heart. Sephadex G-50 column chromatography demonstrated that most of the Ucn-like immunoreactivity in the human heart was eluting earlier than the standard Ucn, with one minor peak in the position for Ucn. Ucn immunoreactivity was not detected in skeletal muscle by immunohistochemistry or RIA. These results suggest that Ucn is produced in the human heart and stored there mainly in the larger molecular weight forms. Endogenously produced Ucn may therefore exert its effects mostly through CRF-R2 in an autocrine and/or paracrine manner in the human heart.

This work was supported in part by a Grant-in-Aid for Cancer Research 7-1 from the Ministry of Health and Welfare, Japan, a Grant-in-Aid for Scientific Research on Priority Area (A-11137301) from The Ministry of Education, Science and Culture, Japan, a Grant-in-Aid for Scientific Research (B-11470047) from the Japan Society for the Promotion of Science, and a grant from The Naitou Foundation and Suzuken Memorial Foundation.

Abbreviations: ANP, Atrial natriuretic peptide; BNP, brain natriuretic peptide; CRF, corticotropin-releasing factor; CRF-R1 or -R2, CRF receptor type 1 or type 2; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; Ucn, urocortin; UCN-LI, Ucn-like immunoreactivity.

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