p38 Kinase rescues failing myocardium after myocardial infarction: evidence for angiogenic and anti-apoptotic mechanisms.
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/mm(2) vs. 1934+/-86/mm(2), 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
Olli
O
Department of Pharmacology and Toxicology, Biocenter Oulu, Finland.
Soini
Ylermi
Y
Ilves
Mika
M
Rysä
Jaana
J
Tuukkanen
Juha
J
Serpi
Raisa
R
Pennanen
Harri
H
Ruskoaho
Heikki
H
Leskinen
Hanna
H
D000256:Adenoviridae; D043925:Angiogenesis Inducing Agents / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004195:Disease Models, Animal; D004562:Electrocardiography; D004789:Enzyme Activation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006333:Heart Failure / Q000209:etiology / Q000628:therapy*; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics; D009203:Myocardial Infarction / Q000150:complications / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics*
D043925:Angiogenesis Inducing Agents; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases