Abstract |
Protection against myocardial ischemia-reperfusion (I/R) injury involves activation of phosphatidylinositol-3-OH kinase (PI3K)- Akt/ protein kinase B and p44/42 mitogen-activated protein kinase (MAPK), components of the reperfusion injury salvage kinase (RISK) pathway. The adipocytokine, apelin, activates PI3K-Akt and p44/42 in various tissues and we, therefore, hypothesised that it might demonstrate cardioprotective activity. Employing both in vivo (open-chest) and in vitro (Langendorff and cardiomyocytes) rodent (mouse and rat) models ofmyocardial I/R injury we investigated if apelin administered at reperfusion at concentrations akin to pharmacological doses possesses cardioprotective activity. Apelin-13 and the physiologically less potent peptide, apelin-36, decreased infarct size in vitro by 39.6% (p<0.01) and 26.1% (p<0.05) respectively. In vivo apelin-13 and apelin-36 reduced infarct size by 43.1% (p<0.01) and 32.7% (p<0.05). LY294002 and UO126, inhibitors of PI3K-Akt and p44/42 phosphorylation respectively, abolished the protective effects of apelin-13 in vitro.Western blot analysis provided further evidence for the involvement of PI3K-Akt and p44/42 in the cardioprotective actions of apelin. In addition, mitochondrial permeability transition pore (MPTP) opening was delayed by both apelin- 13 (127%, p<0.01) and apelin-36 (93%, p<0.01) which, in the case of apelin-13, was inhibited by LY294002 and mitogen-activated protein kinase kinase ( MEK) inhibitor 1. This is the first study to yield evidence that the adipocytokine, apelin, produces direct cardioprotective actions involving the RISK pathway and the MPTP.
|
Authors | James C Simpkin, Derek M Yellon, Sean M Davidson, Shiang Y Lim, Abigail M Wynne, Christopher C T Smith |
Journal | Basic research in cardiology
(Basic Res Cardiol)
Vol. 102
Issue 6
Pg. 518-28
(Nov 2007)
ISSN: 1435-1803 [Electronic] Germany |
PMID | 17694254
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Adipokines
- Apelin
- Apln protein, mouse
- Apln protein, rat
- Cardiotonic Agents
- Carrier Proteins
- Intercellular Signaling Peptides and Proteins
- Mitochondrial Membrane Transport Proteins
- Mitochondrial Permeability Transition Pore
- apelin-13 peptide
- Nitric Oxide Synthase Type III
- Protein Kinases
- Proto-Oncogene Proteins c-akt
- AMP-Activated Protein Kinase Kinases
- Mitogen-Activated Protein Kinase Kinases
|
Topics |
- AMP-Activated Protein Kinase Kinases
- Adipokines
- Animals
- Apelin
- Cardiotonic Agents
(pharmacology)
- Carrier Proteins
(pharmacology)
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Intercellular Signaling Peptides and Proteins
(pharmacology)
- Male
- Mice
- Mice, Inbred C57BL
- Mitochondrial Membrane Transport Proteins
(metabolism)
- Mitochondrial Permeability Transition Pore
- Mitogen-Activated Protein Kinase Kinases
(metabolism)
- Myocardial Infarction
(pathology)
- Myocardial Reperfusion Injury
(metabolism, prevention & control)
- Myocytes, Cardiac
(drug effects, metabolism)
- Nitric Oxide Synthase Type III
(metabolism)
- Phosphatidylinositol 3-Kinases
(metabolism)
- Protein Kinases
(metabolism)
- Proto-Oncogene Proteins c-akt
(metabolism)
- Rats
- Rats, Sprague-Dawley
- Signal Transduction
(drug effects)
|