title: Stress-dependent dilated cardiomyopathy in mice with cardiomyocyte-restricted inactivation of cyclic GMP-dependent protein kinase I.
abstract: OBJECTIVE
  Cardiac hypertrophy is a common and often lethal complication of arterial hypertension. Elevation of myocyte cyclic GMP levels by local actions of endogenous atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) or by pharmacological inhibition of phosphodiesterase-5 was shown to counter-regulate pathological hypertrophy. It was suggested that cGMP-dependent protein kinase I (cGKI) mediates this protective effect, although the role in vivo is under debate. Here, we investigated whether cGKI modulates myocyte growth and/or function in the intact organism.
  
  
  RESULTS
  To circumvent the systemic phenotype associated with germline ablation of cGKI, we inactivated the murine cGKI gene selectively in cardiomyocytes by Cre/loxP-mediated recombination. Mice with cardiomyocyte-restricted cGKI deletion exhibited unaltered cardiac morphology and function under resting conditions. Also, cardiac hypertrophic and contractile responses to β-adrenoreceptor stimulation by isoprenaline (at 40 mg/kg/day during 1 week) were unaltered. However, angiotensin II (Ang II, at 1000 ng/kg/min for 2 weeks) or transverse aortic constriction (for 3 weeks) provoked dilated cardiomyopathy with marked deterioration of cardiac function. This was accompanied by diminished expression of the [Ca(2+)]i-regulating proteins SERCA2a and phospholamban (PLB) and a reduction in PLB phosphorylation at Ser16, the specific target site for cGKI, resulting in altered myocyte Ca(2+)i homeostasis. In isolated adult myocytes, CNP, but not ANP, stimulated PLB phosphorylation, Ca(2+)i-handling, and contractility via cGKI.
  
  
  CONCLUSIONS
  These results indicate that the loss of cGKI in cardiac myocytes compromises the hypertrophic program to pathological stimulation, rendering the heart more susceptible to dysfunction. In particular, cGKI mediates stimulatory effects of CNP on myocyte Ca(2+)i handling and contractility.
authors.affiliation: Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Frantz
authors.forename: Michael
authors.initials: M
authors.lastname: Klaiber
authors.forename: Hideo A
authors.initials: HA
authors.lastname: Baba
authors.forename: Heike
authors.initials: H
authors.lastname: Oberwinkler
authors.forename: Katharina
authors.initials: K
authors.lastname: Völker
authors.forename: Birgit
authors.initials: B
authors.lastname: Gaβner
authors.forename: Barbara
authors.initials: B
authors.lastname: Bayer
authors.forename: Marco
authors.initials: M
authors.lastname: Abeβer
authors.forename: Kai
authors.initials: K
authors.lastname: Schuh
authors.forename: Robert
authors.initials: R
authors.lastname: Feil
authors.forename: Franz
authors.initials: F
authors.lastname: Hofmann
authors.forename: Michaela
authors.initials: M
authors.lastname: Kuhn
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000201:enzymology* / Q000235:genetics; D002316:Cardiotonic Agents / Q000494:pharmacology; D003250:Constriction; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004452:Echocardiography; D017353:Gene Deletion; D006439:Hemodynamics / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D020098:Natriuretic Peptide, C-Type / Q000502:physiology; D010766:Phosphorylation / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D000099211:Phospholamban
chemical_list: D000318:Adrenergic beta-Agonists; D000804:Angiotensin II; D002118:Calcium; D002135:Calcium-Binding Proteins; D002316:Cardiotonic Agents; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D007545:Isoproterenol; D020098:Natriuretic Peptide, C-Type; D014662:Vasoconstrictor Agents; D000099211:Phospholamban