title: Novel insights into the mechanisms mediating the local antihypertrophic effects of cardiac atrial natriuretic peptide: role of cGMP-dependent protein kinase and RGS2.
abstract: Cardiac atrial natriuretic peptide (ANP) locally counteracts cardiac hypertrophy via the guanylyl cyclase-A (GC-A) receptor and cGMP production, but the downstream signalling pathways are unknown. Here, we examined the influence of ANP on beta-adrenergic versus Angiotensin II (Ang II)-dependent (G(s) vs. G(alphaq) mediated) modulation of Ca(2+) (i)-handling in cardiomyocytes and of hypertrophy in intact hearts. L-type Ca(2+) currents and Ca(2+) (i) transients in adult isolated murine ventricular myocytes were studied by voltage-clamp recordings and fluorescence microscopy. ANP suppressed Ang II-stimulated Ca(2+) currents and transients, but had no effect on isoproterenol stimulation. Ang II suppression by ANP was abolished in cardiomyocytes of mice deficient in GC-A, in cyclic GMP-dependent protein kinase I (PKG I) or in the regulator of G protein signalling (RGS) 2, a target of PKG I. Cardiac hypertrophy in response to exogenous Ang II was significantly exacerbated in mice with conditional, cardiomyocyte-restricted GC-A deletion (CM GC-A KO). This was concomitant to increased activation of the Ca(2+)/calmodulin-dependent prohypertrophic signal transducer CaMKII. In contrast, beta-adrenoreceptor-induced hypertrophy was not enhanced in CM GC-A KO mice. Lastly, while the stimulatory effects of Ang II on Ca(2+)-handling were absent in myocytes of mice deficient in TRPC3/TRPC6, the effects of isoproterenol were unchanged. Our data demonstrate a direct myocardial role for ANP/GC-A/cGMP to antagonize the Ca(2+) (i)-dependent hypertrophic growth response to Ang II, but not to beta-adrenergic stimulation. The selectivity of this interaction is determined by PKG I and RGS2-dependent modulation of Ang II/AT(1) signalling. Furthermore, they strengthen published observations in neonatal cardiomyocytes showing that TRPC3/TRPC6 channels are essential for Ang II, but not for beta-adrenergic Ca(2+) (i)-stimulation in adult myocytes.
authors.affiliation: Institute of Physiology, University of Würzburg, Physiologisches Institut der Universität Würzburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Klaiber
authors.forename: Martin
authors.initials: M
authors.lastname: Kruse
authors.forename: Katharina
authors.initials: K
authors.lastname: Völker
authors.forename: Juliane
authors.initials: J
authors.lastname: Schröter
authors.forename: Robert
authors.initials: R
authors.lastname: Feil
authors.forename: Marc
authors.initials: M
authors.lastname: Freichel
authors.forename: Andrea
authors.initials: A
authors.lastname: Gerling
authors.forename: Susanne
authors.initials: S
authors.lastname: Feil
authors.forename: Alexander
authors.initials: A
authors.lastname: Dietrich
authors.forename: Juan Eduardo Camacho
authors.initials: JE
authors.lastname: Londoño
authors.forename: Hideo A
authors.initials: HA
authors.lastname: Baba
authors.forename: Joel
authors.initials: J
authors.lastname: Abramowitz
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Olaf
authors.initials: O
authors.lastname: Pongs
authors.forename: Michaela
authors.initials: M
authors.lastname: Kuhn
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D007668:Kidney / Q000166:cytology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D020710:RGS Proteins / Q000378:metabolism*; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism; D000074287:TRPC6 Cation Channel; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D000318:Adrenergic beta-Agonists; D020710:RGS Proteins; C105345:Rgs2 protein, mouse; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D009320:Atrial Natriuretic Factor; D017869:Cyclic GMP-Dependent Protein Kinases; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D007545:Isoproterenol; D002118:Calcium