Differential regulation of cardiac angiotensin converting enzyme binding sites and AT(1) receptor density in the failing human heart

Article

关键词: HUMAN VENTRICULAR MYOCARDIUM;    FORMING PATHWAYS;    GENE-EXPRESSION;    DOWN-REGULATION;    FAILURE;    CONTRACTION;    MECHANISMS;    INFARCTION;    CAPTOPRIL;   

DOI  :  10.1161/01.CIR.98.17.1735

来源: SCIE

【 摘 要 】

Background-The regulation and interaction of ACE and the angiotensin II (Ang II) type I (AT(1)) receptor in the failing human heart are not understood. Methods and Results-Radioligand binding with H-3-ramiprilat was used to measure ACE protein in membrane preparations of hearts obtained from 36 subjects with idiopathic dilated cardiomyopathy (IDC), 8 subjects with primary pulmonary hypertension (PPH), and 32 organ donors with normal cardiac function (NF hearts) I-125-Ang II formation was measured in a subset of hearts. Saralasin (I-125-{Sar(1),Ile(8)}-Ang II) was used to measure total Ang II receptor density. AT(1) and AT(2) receptor binding were determined with the AT, receptor antagonist losartan. Maximal ACE binding (B-max) was 578+/-47 fmol/mg in IDC left ventricle (LV), 713+/-97 fmol/mg in PPH LV, and 325+/-27 fmol/mg in NF LV (P<0.001, IDC or PPH versus NF). In IDC, PPH, and NF right ventricles (RV), ACE B-max was 737+/-78, 638+/-137, and 422+/-49 fmol/mg, respectively (P=0.02, IDC versus NF; P=0.08, PPH versus NF) I-125-Ang II formation correlated with ACE binding sites (r=0.60, P=0.00005). There was selective downregulation of the AT(1) receptor subtype in failing PPH ventricles: 6.41+/-1.23 fmol/mg in PPH LV, 2.37+/-0.50 fmol/mg in PPH RV, 5.38+/-0.53 fmol/mg in NF LV, and 7.30+/-1.10 fmol/mg in NF RV (P=0.01, PPH RV versus PPH LV; P=0.0006, PPH RV versus NF RV). Conclusions-ACE binding sites are increased in both failing IDC and nonfailing PPH ventricles. In PPH hearts, the AT(1) receptor is downregulated only in the failing RV.

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