衰竭的人类心脏中血管紧张素转换酶结合位点与AT1受体密度的差异调节

Differential regulation of cardiac angiotensin converting enzyme binding sites and AT1 receptor density in the failing human heart.

作者信息

Zisman L S, Asano K, Dutcher D L, Ferdensi A, Robertson A D, Jenkin M, Bush E W, Bohlmeyer T, Perryman M B, Bristow M R

机构信息

Department of Medicine, Division of Cardiology, University of Colorado Health Sciences Center, Denver, Colorado, USA.

出版信息

Circulation. 1998 Oct 27;98(17):1735-41. doi: 10.1161/01.cir.98.17.1735.

DOI:10.1161/01.cir.98.17.1735

PMID:9788827

Abstract

BACKGROUND

The regulation and interaction of ACE and the angiotensin II (Ang II) type I (AT1) receptor in the failing human heart are not understood.

METHODS AND RESULTS

Radioligand binding with 3H-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). 125I-Ang II formation was measured in a subset of hearts. Saralasin (125I-(Sar1,Ile8)-Ang II) was used to measure total Ang II receptor density. AT1 and AT2 receptor binding were determined with the AT1 receptor antagonist losartan. Maximal ACE binding (Bmax) 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 Bmax was 737+/-78, 638+/-137, and 422+/-49 fmol/mg, respectively (P=0.02, IDC versus NF; P=0.08, PPH versus NF). 125I-Ang II formation correlated with ACE binding sites (r=0.60, P=0.00005). There was selective downregulation of the AT1 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 AT1 receptor is downregulated only in the failing RV.

摘要

背景

衰竭的人类心脏中血管紧张素转换酶（ACE）与血管紧张素II（Ang II）1型（AT1）受体的调节及相互作用尚不明确。

方法与结果

采用³H-雷米普利拉放射性配体结合法测定从36例特发性扩张型心肌病（IDC）患者、8例原发性肺动脉高压（PPH）患者以及32例心功能正常的器官捐献者（NF心脏）获取的心脏膜制剂中的ACE蛋白。在部分心脏中测定¹²⁵I-Ang II生成量。使用沙拉新（¹²⁵I-(Sar¹,Ile⁸)-Ang II）测定总Ang II受体密度。用AT1受体拮抗剂氯沙坦测定AT1和AT2受体结合情况。最大ACE结合量（Bmax）在IDC左心室（LV）中为578±47 fmol/mg，在PPH左心室中为713±97 fmol/mg，在NF左心室中为325±27 fmol/mg（P<0.001，IDC或PPH与NF相比）。在IDC、PPH和NF右心室（RV）中，ACE Bmax分别为737±78、638±137和422±49 fmol/mg（P=0.02，IDC与NF相比；P=0.08，PPH与NF相比）。¹²⁵I-Ang II生成量与ACE结合位点相关（r=0.60，P=0.00005）。在衰竭的PPH心室中存在AT1受体亚型的选择性下调：在PPH左心室中为6.41±1.23 fmol/mg，在PPH右心室中为2.37±0.50 fmol/mg，在NF左心室中为5.38±0.53 fmol/mg，在NF右心室中为7.30±1.10 fmol/mg（P=0.01，PPH右心室与PPH左心室相比；P=0.0006，PPH右心室与NF右心室相比）。