title: CaMKII-mediated increased lusitropic responses to beta-adrenoreceptor stimulation in ANP-receptor deficient mice.
abstract: 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 Ca(2+)-handling are preserved and even enhanced. The present study aimed to characterize the specific molecular mechanisms preventing cardiac failure.
  
  
  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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Physiology, University of Würzburg, Röntgenring 9, D-97070 Würzburg, Germany.
authors.forename: Sevdalina
authors.initials: S
authors.lastname: Yurukova
authors.forename: Ana
authors.initials: A
authors.lastname: Kilić
authors.forename: Katharina
authors.initials: K
authors.lastname: Völker
authors.forename: Kirsten
authors.initials: K
authors.lastname: Leineweber
authors.forename: Nataliya
authors.initials: N
authors.lastname: Dybkova
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.forename: Otto-Erich
authors.initials: OE
authors.lastname: Brodde
authors.forename: Michaela
authors.initials: M
authors.lastname: Kuhn
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000032:analysis / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000032:analysis / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000032:analysis / Q000378:metabolism; D004280:Dobutamine / Q000494:pharmacology*; D004789:Enzyme Activation; D006973:Hypertension / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009200:Myocardial Contraction; D010477:Perfusion; D010766:Phosphorylation; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics*; D019837:Ryanodine Receptor Calcium Release Channel / Q000032:analysis / Q000378:metabolism; D013268:Stimulation, Chemical; D000099211:Phospholamban
chemical_list: D000318:Adrenergic beta-Agonists; D002118:Calcium; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D004280:Dobutamine; D017461:Receptors, Atrial Natriuretic Factor; D019837:Ryanodine Receptor Calcium Release Channel; D000099211:Phospholamban