Abstract | BACKGROUND: METHODS: Gene-targeted mice with a cardiomyocyte- or smooth muscle cell-specific deletion of the BK (CMBK or SMBK knockouts) were subjected to the open-chest model of myocardial infarction. Infarct sizes of the conditional mutants were compared with litter-matched controls, global BK knockout, and wild-type 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 myocardial infarction model. RESULTS: Global BK knockouts and CMBK knockouts, in contrast with SMBK knockouts, exhibited significantly larger infarct sizes compared with their respective controls. Ablation of CMBK resulted in higher serum levels of cardiac troponin I and elevated amounts of reactive oxygen species, lower phosphorylated extracellular receptor kinase and phosphorylated AKT levels and an increase in myocardial apoptosis. Moreover, CMBK was required to allow beneficial effects of both nitric oxide-sensitive guanylyl cyclase activation and inhibition of the cGMP-degrading phosphodiesterase-5, ischemic preconditioning, and postconditioning 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 ischemia/reperfusion injury, whereas the pathological events elicited by ischemia/reperfusion do not involve BK in vascular smooth muscle cells. BK seems to permit the protective effects triggered by cinaciguat, riociguat, and different phosphodiesterase-5 inhibitors and beneficial actions of ischemic preconditioning and ischemic postconditioning by a mechanism stemming primarily from cardiomyocytes. This study establishes mitochondrial CMBK channels as a promising target for limiting acute cardiac damage and adverse long-term events that occur after myocardial infarction.
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Authors | Sandra Frankenreiter, Piotr Bednarczyk, Angelina Kniess, Nadja I Bork, Julia Straubinger, Piotr Koprowski, Antoni Wrzosek, Eva Mohr, Angela Logan, Michael P Murphy, Meinrad Gawaz, Thomas Krieg, Adam Szewczyk, Viacheslav O Nikolaev, Peter Ruth, Robert Lukowski |
Journal | Circulation
(Circulation)
Vol. 136
Issue 24
Pg. 2337-2355
(Dec 12 2017)
ISSN: 1524-4539 [Electronic] United States |
PMID | 29051185
(Publication Type: Journal Article)
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Copyright | © 2017 American Heart Association, Inc. |
Chemical References |
- Benzoates
- Cardiotonic Agents
- Large-Conductance Calcium-Activated Potassium Channels
- Pyrazoles
- Pyrimidines
- Nitric Oxide
- BAY 58-2667
- Cyclic AMP-Dependent Protein Kinase Type I
- riociguat
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Topics |
- Animals
- Benzoates
(therapeutic use)
- Cardiotonic Agents
(therapeutic use)
- Cyclic AMP-Dependent Protein Kinase Type I
(metabolism)
- Disease Models, Animal
- Humans
- Ischemic Preconditioning
- Large-Conductance Calcium-Activated Potassium Channels
(genetics, metabolism)
- Mice
- Mice, 129 Strain
- Mice, Inbred C57BL
- Mice, Knockout
- Myocardial Infarction
(drug therapy, physiopathology)
- Myocardium
(pathology)
- Myocytes, Cardiac
(physiology)
- Nitric Oxide
(metabolism)
- Pyrazoles
(therapeutic use)
- Pyrimidines
(therapeutic use)
- Reperfusion Injury
(drug therapy, physiopathology)
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