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Cardioprotection by ischemic postconditioning and cyclic guanosine monophosphate-elevating agents involves cardiomyocyte nitric oxide-sensitive guanylyl cyclase.

Accepted version
Peer-reviewed

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Article

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Authors

Frankenreiter, Sandra 
Groneberg, Dieter 
Kuret, Anna 
Ruth, Peter 

Abstract

AIMS: It has been suggested that the nitric oxide-sensitive guanylyl cyclase (NO-GC)/cyclic guanosine monophosphate (cGMP)-dependent signalling pathway affords protection against cardiac damage during acute myocardial infarction (AMI). It is, however, not clear whether the NO-GC/cGMP system confers its favourable effects through a mechanism located in cardiomyocytes (CMs). The aim of this study was to evaluate the infarct-limiting effects of the endogenous NO-GC in CMs in vivo. METHODS AND RESULTS: Ischemia/reperfusion (I/R) injury was evaluated in mice with a CM-specific deletion of NO-GC (CM NO-GC KO) and in control siblings (CM NO-GC CTR) subjected to an in vivo model of AMI. Lack of CM NO-GC resulted in a mild increase in blood pressure but did not affect basal infarct sizes after I/R. Ischemic postconditioning (iPost), administration of the phosphodiesterase-5 inhibitors sildenafil and tadalafil as well as the NO-GC activator cinaciguat significantly reduced the amount of infarction in control mice but not in CM NO-GC KO littermates. Interestingly, NS11021, an opener of the large-conductance and Ca2+-activated potassium channel (BK), an important downstream effector of cGMP/cGKI in the cardiovascular system, protects I/R-exposed hearts of CM NO-GC proficient and deficient mice. CONCLUSIONS: These findings demonstrate an important role of CM NO-GC for the cardioprotective signalling following AMI in vivo. CM NO-GC function is essential for the beneficial effects on infarct size elicited by iPost and pharmacological elevation of cGMP; however, lack of CM NO-GC does not seem to disrupt the cardioprotection mediated by the BK opener NS11021.

Description

Keywords

Animals, Benzoates, Cyclic GMP, Disease Models, Animal, Enzyme Activators, Female, Ischemic Postconditioning, Large-Conductance Calcium-Activated Potassium Channels, Male, Mice, Knockout, Myocardial Infarction, Myocardial Reperfusion Injury, Myocytes, Cardiac, Nitric Oxide, Phosphodiesterase 5 Inhibitors, Signal Transduction, Sildenafil Citrate, Soluble Guanylyl Cyclase, Tadalafil, Tetrazoles, Thiourea, Time Factors, Up-Regulation

Journal Title

Cardiovasc Res

Conference Name

Journal ISSN

0008-6363
1755-3245

Volume Title

114

Publisher

Oxford University Press (OUP)