Augmentation of cardiac contractility with no change in L-type Ca2+ current in transgenic mice with a cardiac-directed expression of the human adenylyl cyclase type 8 (AC8)

被引:34
作者
Georget, M
Mateo, P
Vandecasteele, G
Jurevicius, J
Lipskaia, L
Defer, N
Hanoune, J
Hoerter, J
Fischmeister, R
机构
[1] Univ Paris Sud, Fac Pharm, INSERM, U446,Lab Cardiol Cellulaire & Mol, F-92296 Chatenay Malabry, France
[2] Hop Henri Mondor, INSERM, U99, Lab Regulat Genes & Signalisat Cellulaire, F-94010 Creteil, France
关键词
cAMP; isolated heart; calcium transient; cell shortening; compartmentation;
D O I
10.1096/fj.02-0292fje
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The beta-adrenergic cascade is severely impaired in heart failure(HF), in part because of a reduction in the activity of the two dominant cardiac adenylyl cyclase (AC) isoforms, AC5 and AC6. Hence, cardiac-directed AC overexpression is a conceivable therapeutic strategy in HF. In this study, we explored the consequences at the cellular and organ level of a cardiac-directed expression of the human AC8 in the transgenic mouse line AC8TG. Unlike AC5 and AC6, which are inhibited by intracellular Ca2+, AC8 is stimulated by Ca2+-calmodulin. Langendorff perfused hearts from AC8TG mice had a twofold higher left ventricular systolic pressure, a 40% faster heart rate, a 37% faster relaxation, and a 30% higher sensitivity to external Ca2+ than nontransgenic control mice (NTG). Cell shortening measured in isolated ventricular myocytes developed 22% faster and relaxed 43% faster in AC8TG than in NTG mice. Likewise, Ca2+ transients measured in fluo-3 AM-loaded myocytes were 30% higher and relaxed 24% faster in AC8TG compared with NTG mice. In spite of the large increase in Ca2+ transients and contraction, expression of AC8 had no effect on the whole-cell L-type Ca2+ current (I-Ca,I-L) amplitude. Moreover, I-Ca,I-L was unchanged even when AC8 was activated by raising intracellular Ca2+. Thus, cardiac expression of AC8 leads to an increase in cAMP that activates specifically Ca2+ uptake into the sarcoplasmic reticulum but not Ca2+ influx at the sarcolemma, suggesting a strong compartmentation of the cAMP signal.
引用
收藏
页码:1636 / +
页数:21
相关论文
共 43 条
[21]  
Liggett SB, 2000, CIRCULATION, V101, P1707
[22]   Enhanced cardiac function in transgenic mice expressing a Ca2+-stimulated adenylyl cyclase [J].
Lipskaia, L ;
Defer, N ;
Esposito, G ;
Hajar, I ;
Garel, MC ;
Rockman, HA ;
Hanoune, J .
CIRCULATION RESEARCH, 2000, 86 (07) :795-801
[23]  
LORENZ JN, 1997, AM J PHYSIOL-HEART C, V273, pH2826
[24]   TARGETED ABLATION OF THE PHOSPHOLAMBAN GENE IS ASSOCIATED WITH MARKEDLY ENHANCED MYOCARDIAL-CONTRACTILITY AND LOSS OF BETA-AGONIST STIMULATION [J].
LUO, WS ;
GRUPP, IL ;
HARRER, J ;
PONNIAH, S ;
GRUPP, G ;
DUFFY, JJ ;
DOETSCHMAN, T ;
KRANIAS, EG .
CIRCULATION RESEARCH, 1994, 75 (03) :401-409
[25]   ENHANCED MYOCARDIAL-FUNCTION IN TRANSGENIC MICE OVEREXPRESSING THE BETA(2)-ADRENERGIC RECEPTOR [J].
MILANO, CA ;
ALLEN, LF ;
ROCKMAN, HA ;
DOLBER, PC ;
MCMINN, TR ;
CHIEN, KR ;
JOHNSON, TD ;
BOND, RA ;
LEFKOWITZ, RJ .
SCIENCE, 1994, 264 (5158) :582-586
[26]   Cardiac protein phosphorylation: functional and pathophysiological correlates [J].
Rapundalo, ST .
CARDIOVASCULAR RESEARCH, 1998, 38 (03) :559-588
[27]   A post-receptor defect of adenylyl cyclase in severely failing myocardium from children with congenital heart disease [J].
Reithmann, C ;
Reber, D ;
KozlikFeldmann, R ;
Netz, H ;
Pilz, G ;
Welz, A ;
Werdan, K .
EUROPEAN JOURNAL OF PHARMACOLOGY, 1997, 330 (01) :79-86
[28]   Cardiac function in genetically engineered mice with altered adrenergic receptor signaling [J].
Rockman, HA ;
Koch, WJ ;
Lefkowitz, RJ .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 1997, 272 (04) :H1553-H1559
[29]   Enhanced myocardial relaxation in vivo in transgenic mice overexpressing the beta(2)-adrenergic receptor is associated with reduced phospholamban protein [J].
Rockman, HA ;
Hamilton, R ;
Jones, LR ;
Milano, CA ;
Mao, L ;
Lefkowitz, RJ .
JOURNAL OF CLINICAL INVESTIGATION, 1996, 97 (07) :1618-1623
[30]   Phospholamban: Protein structure, mechanism of action, and role in cardiac function [J].
Simmerman, HKB ;
Jones, LR .
PHYSIOLOGICAL REVIEWS, 1998, 78 (04) :921-947