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(Circulation Research. 2000;86:377.)
© 2000 American Heart Association, Inc.

Clinical Research

Selective Upregulation of Cardiac Endothelin System in Patients With Ischemic but Not Idiopathic Dilated Cardiomyopathy

Endothelin-1 System in the Human Failing Heart

Presented in part at the 71st Scientific Sessions of the American Heart Association, Dallas, Tex, November 8–11, 1998, and published in abstract form (Circulation. 1998;98[suppl I]:I-768).

Gian Gastone Neri Serneri, Ilaria Cecioni, Simone Vanni, Rita Paniccia, Brunella Bandinelli, Annamaria Vetere, Xiao Janming, Iacopo Bertolozzi, Maria Boddi, Gian Franco Lisi, Guido Sani, Pietro Amedeo Modesti

From the Clinica Medica Generale e Cardiologia (G.G.N.S., I.C., S.V., R.P., B.B., A.V., X.J., I.B., M.B., P.A.M.), University of Florence; Institute of Thoracic and Cardiovascular Surgery (G.F.L.), University of Siena; and Department of Cardiosurgery (G.S.), University of Cagliari, Italy.

Correspondence to Gian Gastone Neri Serneri, Clinica Medica Generale e Cardiologia, University of Florence, Viale Morgagni 85, 50134 Florence, Italy.

Abstract—Only scarce information is available on the activity and modifications of the cardiac endothelin (ET)–1 system in heart failure due to ischemic (ICM) or idiopathic dilated (DCM) cardiomyopathy. The activity of the ET-1 system was investigated by measuring cardiac ET-1 and big ET-1 formation and quantifying cardiac mRNA for prepro–ET-1 (ppET-1), ET-converting enzyme-1, and ET_A and ET_B receptors both in myocardium and in isolated myocytes using Northern blot, reverse transcription–polymerase chain reaction, and in situ hybridization in 22 patients with DCM and 20 with ICM who underwent cardiac transplantation and in 7 potential heart transplant donors (nonfailing hearts). Notwithstanding a similar increase of plasma ET-1 in the 2 groups, cardiac ET formation, mRNA levels for ppET-1, and ET_A and ET_B receptors were higher on both the myocardium and isolated myocytes from ICM than on those from DCM hearts (P<0.001 for all). ppET-1 and ET-converting enzyme-1 mRNAs were expressed on myocytes and endothelial and interstitial cells in ICM, whereas in DCM and nonfailing hearts they were mainly expressed on nonmyocyte cells. In both ICM and DCM, the ET_A mRNA signal was expressed on both myocytes and nonmyocyte cells, whereas ET_B mRNA was almost exclusively localized on nonmyocyte cells. ET_A- and ET_B-specific receptor binding was increased on both myocytes and cardiac membranes, showing a positive correlation with left ventricular ejection fraction in ICM (r=0.78 and 0.70) but not in DCM patients. The present results show that human ventricular myocytes express all of the components of the ET-1 system, which is selectively upregulated in ICM patients and appears to be functionally important in the maintenance of cardiac function.

Key Words: endothelin • heart failure • myocytes • receptors • RNA

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