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

TitlecGMP-Elevating Compounds and Ischemic Conditioning Provide Cardioprotection Against Ischemia and Reperfusion Injury via Cardiomyocyte-Specific BK Channels.
Publication TypeJournal Article
Year of Publication2017
AuthorsFrankenreiter, S, Bednarczyk, P, Kniess, A, Bork, N, Straubinger, J, Koprowski, P, Wrzosek, A, Mohr, E, Logan, A, Murphy, MP, Gawaz, M, Krieg, T, Szewczyk, A, Nikolaev, VO, Ruth, P, Lukowski, R
JournalCirculation
Date Published2017 Oct 19
ISSN1524-4539
Abstract

Background -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 Ca(2+)-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. Methods -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. Results -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. Conclusions -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.

DOI10.1161/CIRCULATIONAHA.117.028723
Alternate JournalCirculation
Citation Key10.1161/CIRCULATIONAHA.117.028723
PubMed ID29051185