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cGKI signaling in cardiac hypertrophy

The atrial natriuretic peptide (ANP) has been shown to modulate hypertrophy of the heart via the cardiac NP receptor guanylyl cyclase-A (GC-A) [1]. Also, analysis of transgenic mice with a cardiomyocyte (cM) specific overexpression of GC-A and the chronic inhibition of the cGMP-degrading phosphodiesterase-5 by sildenafil indicated that the second messenger cGMP can blunt hypertrophic signals from pressure load and neurohormonal stress perhaps by activation of a cardiac cGMP kinase I (cGKI) pathway [24]. To test whether the predicted hypertrophic phenotype of transgenic animals carrying a genetic disruption of cGKI in the heart can be confirmed, we analyzed the recently established cGKI rescue mice (RM) [5]. We provide strong evidence that the cGKI protein is not present in cM of RM, whereas it is detectable in the myocardium of control mice. We studied hypertrophy in response to chronic β-adrenoreceptor stimulation by isoproterenol (ISO) and identified significantly reduced expression levels of the β1-adrenergic receptor in the hearts of gene-targeted RM as compared to littermate controls. However, the heart/body weight ratios (HW/BW) and the mean cM cross-section area were increased to a similar extent in both genotypes after the 7 days of ISO (30 mg/kg/d). Up-regulation of fetal gene markers (NPPA, Myh7, PI-16) and down-regulation of genes which are normally expressed in the adult heart (Myh6, Serca2), both indicative for pathological hypertrophy, were as well not altered by the lack of cGKI in cM.

In summary, the presented data indicates that cGKI signaling in cM does not protect the heart from the maladaptive hypertrophy program induced by chronic β-adrenergic stimulation that activates Gs protein-coupled receptor pathways.


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The authors acknowledge the technical support of Sabine Brummer and Teodora Kennel. We thank Dr. Veronika Leiss and Florian Loga for performing confocal laser microscopy and semi-quantitative RT-PCR analysis. We are grateful to Dr. Joe Beavo and Dr. Sergei Rybalkin for the continuous discussions and making the PDE-5 antibodies available. This work was supported by the Deutsche Forschungsgemeinschaft FOR923.

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Correspondence to Robert Lukowski.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Lukowski, R., Hofmann, F. cGKI signaling in cardiac hypertrophy. BMC Pharmacol 9 (Suppl 1), S26 (2009).

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