Journal Article

CaMKII-mediated increased lusitropic responses to β-adrenoreceptor stimulation in ANP-receptor deficient mice

Sevdalina Yurukova, Ana Kilić, Katharina Völker, Kirsten Leineweber, Nataliya Dybkova, Lars S. Maier, Otto-Erich Brodde and Michaela Kuhn

in Cardiovascular Research

Published on behalf of European Society of Cardiology

Volume 73, issue 4, pages 678-688
Published in print March 2007 | ISSN: 0008-6363
Published online March 2007 | e-ISSN: 1755-3245 | DOI:
CaMKII-mediated increased lusitropic responses to β-adrenoreceptor stimulation in ANP-receptor deficient mice

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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

Journal Article.  6574 words.  Illustrated.

Subjects: Cardiovascular Medicine

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