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

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 sGC? subunit, which binds to the common sGC?1 subunit, exists in two different isoforms, sGC?1 and sGC?2, but their relative physiological roles remain unknown. In the present study, we studied Langendorff-perfused isolated hearts of genetically engineered mice lacking functional sGC?1 (sGC?1KO mice), which is the predominant isoform in the heart. Our results show that the loss of sGC?1 has a positive inotropic and lusitropic effect on basal cardiac function, indicating an important role for sGC?1 in regulating basal myocardial contractility. Surprisingly, IPC led to a similar 35-40% reduction in infarct size and concomitant protein kinase C? (PKC?) phosphorylation in both wild-type (WT) and sGC?1KO 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 ?mol/L) completely abolished the protection by IPC in WT and sGC?1KO hearts. NO-stimulated cGMP production was severely attenuated in sGC?1KO hearts compared to WT hearts, indicating that the sGC?2 isoform only produces minute amounts of cGMP after NO stimulation. Taken together, our results indicate that although sGC?1 importantly regulates cardiac contractility, it is not required for cardioprotection by IPC. Instead, our results suggest that possibly only minimal sGC activity, which in sGC?1KO hearts is provided by the sGC?2 isoform, is sufficient to transduce the cardioprotective signal induced by IPC via phosphorylation of PKC?.

SUBMITTER: Sips PY

PROVIDER: S-EPMC3375061 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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

Sips Patrick Y PY Brouckaert Peter P Ichinose Fumito F

Basic research in cardiology 20110311 4

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 lack ...[more]

PMID: 21394564

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

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