Protection through postconditioning or a mitochondria-targeted S-nitrosothiol is unaffected by cardiomyocyte-selective ablation of protein kinase G
Abstract
Protein kinase G type I (PKGI) plays a critical role in survival signaling of pre- and postconditioning downstream of cardiac cGMP. However, it is unclear whether PKGI exerts its protective effects in the cardiomyocyte or if other cardiac cell types are involved, and whether nitric oxide (NO) metabolism can target cardiomyocyte mitochondria independently of cGMP/PKGI. We tested whether protection against reperfusion injury by ischemic postconditioning (IPost), soluble guanylyl cyclase (sGC) activation and inhibition, adenosine A(2B) receptor (A(2B)AR) agonist, phosphodiesterase type-5 (PDE-5) inhibitor, or mitochondria-targeted S-nitrosothiol (MitoSNO) was affected by a cardiomyocyte-specific ablation of the PKGI gene in the mouse (CMG-KO). In situ hearts underwent 30 min of regional ischemia followed by 2 h of reperfusion. As expected, in CMG-CTRs all interventions at early reperfusion lead to profound infarct size reduction: IPost (six cycles of 10-s reperfusion and 10-s coronary occlusion) with or without treatment with the sGC inhibitor ODQ, treatment with the specific sGC activator BAY58-2667 (BAY58), the selective A(2B)AR agonist BAY60-6583 (BAY60), PDE-5 inhibitor sildenafil, and MitoSNO. MitoSNO accumulates within mitochondria, driven by the membrane potential, where it generates NO· and S-nitrosates thiol proteins. In contrast, the hearts of CMG-KO animals were not protected by BAY58 and sildenafil, whereas the protective effects of IPost, IPost with ODQ, BAY60, and MitoSNO were unaffected by the lack of PKGI. Taken together, PKGI is important for the protection against ischemia reperfusion injury afforded by sGC activation or PDE-5 inhibition. However, the beneficial effects of IPost, activation of the A(2B)AR, as well as the direct effects via mitochondrial S-nitrosation do not depend on PKGI in cardiomyocytes.
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MitoSNO cardioprotection is not due to nonmitochondrial cyclic GMP-protein kinase G pathways, because MitoSNO protected mice with cardiomyocyte protein kinase G deficiency.
“MitoSNO has been reported to be protective in mice with cardiomyocyte deficiency of protein kinase G18, indicating that the cardio-protection conferred by MitoSNO is not due to nonmitochondrial pathways that operate through cyclic GMP–protein kinase G signaling3,6”
From Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I (2013) · cites this paper as [18]
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- Authors
- Methner, C., Lukowski, R., Grube, K., Loga, F., Smith, R. A. J., Murphy, M. P., Hofmann, F., & Krieg, T.
- Affiliations
- University of Cambridge (GB)
- Universitätsmedizin Greifswald (DE)
- Technical University of Munich (DE)
- University of Otago (NZ)
- MRC Mitochondrial Biology Unit (GB)
- Corresponding author
- Krieg, Thomas
- Venue
- Basic Research in Cardiology
- Published
- 2013-02-20
- Volume
- 108
- Issue
- 2
- Pages
- 337-337
- ISSN
- 0003-9217 (ISSN-L)
- 0300-8428
- 1435-1803
- OpenAlex
- W1982607624
- Cited by
- 62
- References
- 26
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 1 · 2021: 6 · 2020: 4 · 2019: 3 · 2018: 5 · 2017: 3 · 2016: 3 · 2015: 11 · 2014: 14 · 2013: 5
- FWCI
- 8.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Basic Research in Cardiology (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Funders
- British Heart Foundation (PG/12/42/29655)
- Bayer HealthCare
- Deutscher Akademischer Austauschdienst
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Keywords
- cardiomyocyte-specific knockout, ischemic postconditioning, ischemia-reperfusion injury, soluble guanylate cyclase, adenosine A2B receptor, phosphodiesterase-5 inhibition, sildenafil, nitric oxide metabolism, infarct size, cardioprotection
- MeSH terms
- Sildenafil Citrate, Animals, Benzoates, Heart, Immunohistochemistry, Mice, Inbred C57BL, Mitochondria, Myocardium, Piperazines, Purines, Sulfones, Blotting, Western, Myocardial Reperfusion Injury, Cyclic GMP-Dependent Protein Kinases, Mice, Knockout, S-Nitrosothiols, Myocytes, Cardiac, Mice, Ischemic Postconditioning, Phosphodiesterase 5 Inhibitors
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