Copyright © 2007, European Society of Cardiology
CaMKII-mediated increased lusitropic responses to β-adrenoreceptor stimulation in ANP-receptor deficient mice
a,1
aInstitute of Physiology, University of Würzburg, Röntgenring 9, D-97070 Würzburg, Germany
bDepartment of Pathophysiology and Nephrology, University of Essen School of Medicine, Germany
cDepartment of Cardiology and Pneumology/Heart Center, Georg-August-University of Göttingen, Germany
* Corresponding author. Tel.: +49 931 31 2720; fax: +49 931 31 2741. Email address: michaela.kuhn{at}mail.uni-wuerzburg.de
Objective: Mice with genetic disruption of the guanylyl cyclase-A (GC-A) receptor for atrial natriuretic peptide (ANP), have chronic arterial hypertension and marked cardiac hypertrophy. Intriguingly, despite pronounced remodeling, cardiac contractile functions and cardiomyocyte Ca2+-handling are preserved and even enhanced. The present study aimed to characterize the specific molecular mechanisms preventing cardiac failure.
Methods and results: Contractile function and expression as well as phosphorylation of regulatory proteins were evaluated in isolated perfused working hearts from wild-type and GC-A KO mice under baseline conditions and during β1-adrenergic stimulation. Cai2+-transients were monitored in Indo-1 loaded isolated adult cardiomyocytes. Cardiac contractile, especially lusitropic responsiveness to β-adrenergic stimulation was significantly increased in GC-A KO mice. This was concomitant to enhanced expression and activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII), increased dual-site phosphorylation of phospholamban (PLB) at Ser16 and Thr17, enhanced amplitude of Cai2+ transients, and accelerated Cai2+ decay. In contrast, the expression of cardiac ryanodine receptors and phosphorylation at Ser2809 and Ser2815 was not altered. Pharmacological inhibition of CaMKII-but not of protein kinase A-mediated PLB phosphorylation totally abolished the increased effects of β-adrenergic stimulation on cardiac contractility and Cai2+-handling. Thus, acceleration of sarcoplasmic reticulum Ca2+-uptake and increased availability of Ca2+ for contraction, both secondary to increased CaMKII-mediated PLB phosphorylation, seem to mediate the augmented responsiveness of GC-A KO hearts to catecholamines.
Conclusion: Our observations show that increased CaMKII activity enhances the contractile relaxation response of hypertrophic GC-A KO hearts to β-adrenergic stimulation and emphasize the critical role of CaMKII-dependent pathways in β1-adrenoreceptor modulation of myocardial Ca2+-homeostasis and contractility.
KEYWORDS Atrial natriuretic peptide; Guanylyl cyclase-A; Cyclic GMP; CaMKII; Calcium cycling; Phospholamban; Heart failure
1 Contributed equally to this manuscript.