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
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