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01-07-2011 | Original Contribution

The alpha1 isoform of soluble guanylate cyclase regulates cardiac contractility but is not required for ischemic preconditioning

Authors: Patrick Y. Sips, Peter Brouckaert, Fumito Ichinose

Published in: Basic Research in Cardiology | Issue 4/2011

Abstract

Nitric oxide (NO)-dependent soluble guanylate cyclase (sGC) activation is an important component of cardiac signal transduction pathways, including the cardioprotective signaling cascade induced by ischemic preconditioning (IPC). The sGCα subunit, which binds to the common sGCβ1 subunit, exists in two different isoforms, sGCα1 and sGCα2, but their relative physiological roles remain unknown. In the present study, we studied Langendorff-perfused isolated hearts of genetically engineered mice lacking functional sGCα1 (sGCα1KO mice), which is the predominant isoform in the heart. Our results show that the loss of sGCα1 has a positive inotropic and lusitropic effect on basal cardiac function, indicating an important role for sGCα1 in regulating basal myocardial contractility. Surprisingly, IPC led to a similar 35–40% reduction in infarct size and concomitant protein kinase Cε (PKCε) phosphorylation in both wild-type (WT) and sGCα1KO hearts subjected to 40 min of global ischemia and reperfusion. Inhibition of the activation of all sGC isoforms by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ, 10 μmol/L) completely abolished the protection by IPC in WT and sGCα1KO hearts. NO-stimulated cGMP production was severely attenuated in sGCα1KO hearts compared to WT hearts, indicating that the sGCα2 isoform only produces minute amounts of cGMP after NO stimulation. Taken together, our results indicate that although sGCα1 importantly regulates cardiac contractility, it is not required for cardioprotection by IPC. Instead, our results suggest that possibly only minimal sGC activity, which in sGCα1KO hearts is provided by the sGCα2 isoform, is sufficient to transduce the cardioprotective signal induced by IPC via phosphorylation of PKCε.

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Title: The alpha1 isoform of soluble guanylate cyclase regulates cardiac contractility but is not required for ischemic preconditioning
Authors: Patrick Y. Sips
Peter Brouckaert
Fumito Ichinose
Publication date: 01-07-2011
Publisher: Springer-Verlag
Published in: Basic Research in Cardiology / Issue 4/2011
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-011-0167-y

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