cGMP-Elevating Compounds and Ischemic Conditioning Provide Cardioprotection Against Ischemia and Reperfusion Injury via Cardiomyocyte-Specific BK Channels

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The nitric oxide-sensitive guanylyl cyclase (NO-GC)/cyclic guanosine-3',5'-monophosphate (cGMP)/cGMP-dependent protein kinase type I (cGKI)-signaling pathway can afford protection against the ischemia and reperfusion (I/R) injury that occurs during myocardial infarction (MI). Reportedly, voltage and Ca2+-activated K+ channels of the BK-type are stimulated by cGMP/cGKI and recent ex-vivo studies implicated that increased BK activity favors the survival of the myocardium at I/R. It remains unclear, however, whether the molecular events downstream of cGMP involve BK channels present in cardiomyocytes (CMs) or in other cardiac cell types.


Gene-targeted mice with a CM- or smooth muscle (SM) cell-specific deletion of the BK were subjected to the open-chest model of MI. Infarct sizes of the conditional mutants were compared to litter-matched controls as well as to global BK knockout (BK-KO) and wildtype mice. Cardiac damage was assessed after mechanical conditioning or pharmacological stimulation of the cGMP pathway and by using direct modulators of BK. Long-term outcome was studied with respect to heart functions and cardiac fibrosis in a chronic MI model.


Global BK-KOs as well as CMBK-KOs, in contrast to SMBK-KOs, exhibited significantly larger infarct sizes as compared to their respective controls. Ablation of CMBK resulted in higher serum levels of cardiac troponin I as well as elevated amounts of reactive oxygen species, lower p-ERK/p-AKT levels and an increase in myocardial apoptosis. Moreover, CMBK was required to allow beneficial effects of both NO-GC activation and inhibition of the cGMP-degrading phosphodiesterase-5 (PDE5) as well as ischemic pre- (iPre) and postconditioning (iPost) regimens. To this end, after 4 weeks of reperfusion fibrotic tissue increased and myocardial strain echocardiography was significantly compromised in CMBK-deficient mice.


Lack of CMBK channels renders the heart more susceptible to I/R injury, whereas the pathologic events elicited by I/R do not involve BK in SM. BK seems to permit the protective effects triggered by cinaciguat, riociguat and different PDE5 inhibitors as well as beneficial actions of iPre and iPost by a mechanism stemming primarily from CMs. In summary, this study establishes mitochondrial CMBK channels as a promising target for limiting acute cardiac damage as well as adverse long-term events that occur after MI.

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