Differential regulation of cardiac angiotensin converting enzyme binding sites and AT1 receptor density in the failing human heart.
Differential regulation of cardiac angiotensin converting enzyme binding sites and AT1 receptor density in the failing human heart.
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DOI：
10.1161/01.cir.98.17.1735
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发表时间：
1998-10
期刊：
影响因子：
37.8
通讯作者：
Lawrence S. Zisman;Koji Asano;Darrin L. Dutcher;Anthony Ferdensi;A. Robertson;M. Jenkin;Erik W. Bush;T. Bohlmeyer;M. Perryman;Michael R. Bristow
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文献类型：
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作者：
Lawrence S. Zisman;Koji Asano;Darrin L. Dutcher;Anthony Ferdensi;A. Robertson;M. Jenkin;Erik W. Bush;T. Bohlmeyer;M. Perryman;Michael R. Bristow
背景ACE和血管紧张素II (Ang II) I型（AT1）受体在人类衰竭心脏中的调控和相互作用尚不清楚。方法与结果采用放射配体结合3h -雷米普利特检测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）患者和32例心功能正常器官供者心脏膜制剂中的ACE蛋白。在一部分心脏中测量了125I-Ang II的形成。用Saralasin （125I-(Sar1,Ile8)-Ang II）测定Ang II总受体密度。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（Bmax）在IDC左心室（LV）为578+/-47 fmol/mg， PPH左心室为713+/-97 fmol/mg， NF左心室为325+/-27 fmol/mg （IDC或PPH与NF比较，P<0.001）。在IDC、PPH和NF右心室，ACE Bmax分别为737+/-78、638+/-137和422+/-49 fmol/mg （IDC vs . NF P=0.02; PPH vs . NF P=0.08）。125I-Ang II的形成与ACE结合位点相关（r=0.60， P=0.00005）。衰竭PPH心室中AT1受体亚型有选择性下调：PPH左室6.41+/-1.23 fmol/mg， PPH右室2.37+/-0.50 fmol/mg， NF左室5.38+/-0.53 fmol/mg， NF右室7.30+/-1.10 fmol/mg （PPH RV vs PPH LV P=0.01, PPH RV vs NF RV P=0.0006）。结论：在失败的IDC和未失败的PPH心室中，ACE结合位点均增加。在PPH心脏中，AT1受体仅在衰竭的右心室中下调。
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.