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

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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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Acknowledgments

This work was supported by the Resuscitation Fellowship Award from the American Heart Association and Philips (P.Y.Sips) and by National Institute of Health grant GM079360 (F.Ichinose). The authors would like to thank Kentaro Tokuda for technical assistance in harvesting isolated cardiomyocytes.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, 149, 13th Street, Room 4312, Charlestown, MA, 02129, USA

    Patrick Y. Sips & Fumito Ichinose

  2. Department of Medical Molecular Biology, Ghent University, Ghent, Belgium

    Peter Brouckaert

  3. Department for Molecular Biomedical Research, Flanders Institute for Biotechnology, Technologiepark 927, 9052, Ghent, Belgium

    Peter Brouckaert

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  1. Patrick Y. Sips
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Sips, P.Y., Brouckaert, P. & Ichinose, F. The alpha1 isoform of soluble guanylate cyclase regulates cardiac contractility but is not required for ischemic preconditioning. Basic Res Cardiol 106, 635–643 (2011). https://doi.org/10.1007/s00395-011-0167-y

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