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This Article Summary Full Text Full Text (PDF) Supplemental Data All Versions of this Article: fj.05-5618fjev1 20/11/1907    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tenhunen, O. Articles by Leskinen, H. Search for Related Content PubMed PubMed Citation Articles by Tenhunen, O. Articles by Leskinen, H.

p38 Kinase rescues failing myocardium after myocardial infarction: evidence for angiogenic and anti-apoptotic mechanisms

Olli Tenhunen^*, Ylermi Soini, Mika Ilves, Jaana Rysä^*, Juha Tuukkanen, Raisa Serpi^*, Harri Pennanen^*, Heikki Ruskoaho^*,1 and Hanna Leskinen^*

Departments of
^* Pharmacology and Toxicology, Biocenter Oulu;

Pathology;

Physiology and

Anatomy and Cell Biology, University of Oulu, Oulu, Finland

¹Correspondence: Department of Pharmacology and Toxicology, Faculty of Medicine, University of Oulu, P.O. Box 5000, University of Oulu, Oulu, FIN-90014, Finland. E-mail: heikki.ruskoaho{at}oulu.fi

ABSTRACT

As a leading cause of heart failure, postinfarction left ventricular remodeling represents an important target for therapeutic interventions. Mitogen-activated protein kinases regulate critical cellular processes including stress response and survival, but their role in left ventricular remodeling is unknown. In the present study, rats were subjected to myocardial infarction by ligating the left anterior descending coronary artery. Western blot and kinase assay analysis revealed an inactivation of p38 kinase after myocardial infarction. Local adenovirus-mediated cotransfection of wild-type (WT) p38 kinase and constitutively active MKK3b reduced infarct size (26±3% vs. 47±4%, P<0.05 vs. LacZ-treated control) associated with improved ejection fraction (66.9±5.5% vs. 44.4±4.0%, P<0.001), fractional shortening (30.2±2.1% vs. 19.7±2.2%, P<0.001), and decreased left ventricular diastolic diameter (8.5±0.4 mm vs. 9.5±0.2 mm, P<0.01). p38 kinase gene transfer increased capillary density (2423±107/mm² vs. 1934±86/mm², P<0.001) and resulted in microvessel enlargement in the ischemic border zone. Apoptosis (35±7 vs. 69±13 cells, P<0.01) and fibrosis (16±3% vs. 34±8%, P<0.05) were reduced, while the number of c-kit positive cardiac stem-like cells remained unchanged. These results indicate that reduced p38 signaling predisposes to adverse postinfarction remodeling. The rescue of failing myocardium with p38 kinase may be a potential new therapy for heart failure after myocardial infarction. —Tenhunen, O., Soini, Y., Ilves, M., Rysä, J., Tuukkanen, J., Serpi, R., Pennanen, H., Ruskoaho, H., Leskinen, H. p38 Kinase rescues failing myocardium after myocardial infarction: evidence for angiogenic and anti-apoptotic mechanisms.

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