H11 Kinase Prevents Myocardial Infarction by Preemptive Preconditioning of the Heart
| Autor: | Amy M. Shah, Xiangzhen Sui, Vinciane Gaussin, Michel Pelat, Nadia Hedhli, Hongyu Qiu, Chull Hong, Audrey Ginion, Thomas Wagner, Stephen F. Vatner, Luc Bertrand, Li Wang, Christophe Depre |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
medicine.medical_specialty
Cell Survival Physiology Myocardial Infarction Ischemia Muscle Proteins Apoptosis Mice Transgenic AMP-Activated Protein Kinases Protein Serine-Threonine Kinases Pharmacology Mice Phosphatidylinositol 3-Kinases Multienzyme Complexes Internal medicine medicine Animals HSP20 Heat-Shock Proteins Myocytes Cardiac Phosphorylation Protein kinase A Glycogen synthase Protein kinase B Cells Cultured Heat-Shock Proteins Cardioprotection biology Kinase business.industry AMPK medicine.disease Cytoprotection Ischemic Preconditioning Myocardial Cardiology biology.protein Ischemic preconditioning Cardiology and Cardiovascular Medicine business Proto-Oncogene Proteins c-akt Molecular Chaperones |
| Zdroj: | Circulation Research. 98:280-288 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/01.res.0000201284.45482.e8 |
| Popis: | Ischemic preconditioning confers powerful protection against myocardial infarction through pre-emptive activation of survival signaling pathways, but it remains difficult to apply to patients with ischemic heart disease, and its effects are transient. Promoting a sustained activation of preconditioning mechanisms in vivo would represent a novel approach of cardioprotection. We tested the role of the protein H11 kinase (H11K), which accumulates by 4- to 6-fold in myocardium of patients with chronic ischemic heart disease and in experimental models of ischemia. This increased expression was quantitatively reproduced in cardiac myocytes using a transgenic (TG) mouse model. After 45 minutes of coronary artery occlusion and reperfusion, hearts from TG mice showed an 82+/-5% reduction in infarct size compared with wild-type (WT), which was similar to the 84+/-4% reduction of infarct size observed in WT after a protocol of ischemic preconditioning. Hearts from TG mice showed significant activation of survival kinases participating in preconditioning, including Akt and the 5'AMP-activated protein kinase (AMPK). H11K directly binds to both Akt and AMPK and promotes their nuclear translocation and their association in a multiprotein complex, which results in a stimulation of survival mechanisms in cytosol and nucleus, including inhibition of proapoptotic effectors (glycogen synthase kinase-3beta, Bad, and Foxo), activation of antiapoptotic effectors (protein kinase Cepsilon, endothelial and inducible NO synthase isoforms, and heat shock protein 70), increased expression of the hypoxia-inducible factor-1alpha, and genomic switch to glucose utilization. Therefore, activation of survival pathways by H11K preemptively triggers the antiapoptotic and metabolic response to ischemia and is sufficient to confer cardioprotection in vivo equally potent to preconditioning. |
| Databáze: | OpenAIRE |
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