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Tytuł pozycji:

Protection through postconditioning or a mitochondria-targeted S-nitrosothiol is unaffected by cardiomyocyte-selective ablation of protein kinase G.

Tytuł:
Protection through postconditioning or a mitochondria-targeted S-nitrosothiol is unaffected by cardiomyocyte-selective ablation of protein kinase G.
Autorzy:
Methner C; Department of Medicine, University of Cambridge, Addenbrooke's Hospital Box 110, Cambridge CB2 2QQ, UK.
Lukowski R
Grube K
Loga F
Smith RA
Murphy MP
Hofmann F
Krieg T
Źródło:
Basic research in cardiology [Basic Res Cardiol] 2013 Mar; Vol. 108 (2), pp. 337. Date of Electronic Publication: 2013 Feb 20.
Typ publikacji:
Journal Article; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Original Publication: Darmstadt, Steinkopff.
MeSH Terms:
Benzoates/*pharmacology
Cyclic GMP-Dependent Protein Kinases/*metabolism
Ischemic Postconditioning/*methods
Myocardial Reperfusion Injury/*prevention & control
Piperazines/*pharmacology
S-Nitrosothiols/*pharmacology
Sulfones/*pharmacology
Animals ; Benzoates/metabolism ; Blotting, Western ; Heart/drug effects ; Immunohistochemistry ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/metabolism ; Myocardial Reperfusion Injury/metabolism ; Myocardial Reperfusion Injury/physiopathology ; Myocardium/pathology ; Myocytes, Cardiac/metabolism ; Phosphodiesterase 5 Inhibitors/metabolism ; Phosphodiesterase 5 Inhibitors/pharmacology ; Piperazines/metabolism ; Purines/metabolism ; Purines/pharmacology ; S-Nitrosothiols/metabolism ; Sildenafil Citrate ; Sulfones/metabolism
Grant Information:
MC_U105663142 United Kingdom MRC_ Medical Research Council; PG/12/42/29655 United Kingdom BHF_ British Heart Foundation
Substance Nomenclature:
0 (Benzoates)
0 (Phosphodiesterase 5 Inhibitors)
0 (Piperazines)
0 (Purines)
0 (S-Nitrosothiols)
0 (Sulfones)
329773-35-5 (BAY 58-2667)
BW9B0ZE037 (Sildenafil Citrate)
EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases)
Entry Date(s):
Date Created: 20130221 Date Completed: 20130718 Latest Revision: 20211021
Update Code:
20240104
DOI:
10.1007/s00395-013-0337-1
PMID:
23423145
Czasopismo naukowe
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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