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

Autor: Otto-Erich Brodde, Michaela Kuhn, Nataliya Dybkova, Ana Kilic, Kirsten Leineweber, Sevdalina Yurukova, Katharina Völker, Lars S. Maier
Rok vydání: 2007
Předmět:
medicine.medical_specialty
Lusitropy
Physiology
Blotting
Western
Cardiomegaly
Stimulation
030204 cardiovascular system & hematology
Biology
Contractility
Mice
03 medical and health sciences
0302 clinical medicine
Atrial natriuretic peptide
Dobutamine
Physiology (medical)
Ca2+/calmodulin-dependent protein kinase
Internal medicine
medicine
Animals
Phosphorylation
Protein kinase A
030304 developmental biology
Mice
Knockout
0303 health sciences
Ryanodine receptor
Calcium-Binding Proteins
Ryanodine Receptor Calcium Release Channel
Adrenergic beta-Agonists
Cyclic AMP-Dependent Protein Kinases
Myocardial Contraction
Stimulation
Chemical
Phospholamban
Enzyme Activation
Perfusion
Endocrinology
Calcium-Calmodulin-Dependent Protein Kinases
Hypertension
Models
Animal
cardiovascular system
Calcium
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Cardiology and Cardiovascular Medicine
Receptors
Atrial Natriuretic Factor
Zdroj: Cardiovascular Research. 73:678-688
ISSN: 1755-3245
0008-6363
DOI: 10.1016/j.cardiores.2006.10.003
Popis: 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 Ca(2+)-handling are preserved and even enhanced. The present study aimed to characterize the specific molecular mechanisms preventing cardiac failure.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 beta(1)-adrenergic stimulation. Ca(i)(2+)-transients were monitored in Indo-1 loaded isolated adult cardiomyocytes. Cardiac contractile, especially lusitropic responsiveness to beta-adrenergic stimulation was significantly increased in GC-A KO mice. This was concomitant to enhanced expression and activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), increased dual-site phosphorylation of phospholamban (PLB) at Ser(16) and Thr(17), enhanced amplitude of Ca(i)(2+) transients, and accelerated Ca(i)(2+) decay. In contrast, the expression of cardiac ryanodine receptors and phosphorylation at Ser(2809) and Ser(2815) was not altered. Pharmacological inhibition of CaMKII-but not of protein kinase A-mediated PLB phosphorylation totally abolished the increased effects of beta-adrenergic stimulation on cardiac contractility and Ca(i)(2+)-handling. Thus, acceleration of sarcoplasmic reticulum Ca(2+)-uptake and increased availability of Ca(2+) for contraction, both secondary to increased CaMKII-mediated PLB phosphorylation, seem to mediate the augmented responsiveness of GC-A KO hearts to catecholamines.Our observations show that increased CaMKII activity enhances the contractile relaxation response of hypertrophic GC-A KO hearts to beta-adrenergic stimulation and emphasize the critical role of CaMKII-dependent pathways in beta(1)-adrenoreceptor modulation of myocardial Ca(2+)-homeostasis and contractility.
Databáze: OpenAIRE
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