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

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• 作者：Sevdalina Yurukova ; Ana Kilić ; Katharina Vö ; lker ; Kirsten Leineweber ; Nataliya Dybkova ; Lars S. Maier ; Otto-Erich Brodde ; Michaela Kuhn
• 关键词：Atrial natriuretic peptide ; Guanylyl cyclase-A ; Cyclic GMP ; CaMKII ; Calcium cycling ; Phospholamban ; Heart failure
• 刊名：Cardiovascular Research
• 出版年：2007
• 期刊代码：48_00086363
• 类别：med
• 出版时间：1 March 2007
• 卷：73
• 期：4
• 页码：678-688
• 文件大小：692 K

摘要

>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. Ca_i²⁺-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 Ca_i²⁺ transients, and accelerated Ca_i²⁺ 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 Ca_i²⁺-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.