CTGF/CCN2 Postconditioning Increases Tolerance of Murine Hearts towards Ischemia-Reperfusion Injury
| Autor: | Else Marie Valbjørn Hagelin, Mohammad Shakil Ahmed, Ole Jørgen Kaasbøll, Håvard Attramadal, Ingvild Tronstad Moe, Espen Stang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Critical Care and Emergency Medicine Myocardial Infarction lcsh:Medicine 030204 cardiovascular system & hematology Cardiovascular Medicine Vascular Medicine Glycogen Synthase Kinase 3 0302 clinical medicine GSK-3 Ischemia Animal Cells Heart Rate Medicine and Health Sciences Myocyte Phosphorylation lcsh:Science Ischemic Postconditioning Cells Cultured Phosphoinositide-3 Kinase Inhibitors Multidisciplinary Kinase Heart Recombinant Proteins Cardiovascular physiology Cardiovascular Diseases Anatomy Cellular Types Research Article medicine.medical_specialty Morpholines Muscle Tissue Cardiology Myocardial Reperfusion Injury Cardiovascular Pharmacology 03 medical and health sciences Internal medicine medicine Animals Humans GSK3B Pharmacology Muscle Cells Glycogen Synthase Kinase 3 beta business.industry Myocardium lcsh:R Connective Tissue Growth Factor Biology and Life Sciences Cell Biology medicine.disease CTGF Mice Inbred C57BL 030104 developmental biology Endocrinology Biological Tissue Chromones Reperfusion Cardiovascular Anatomy lcsh:Q business Reperfusion injury |
| Zdroj: | PLoS ONE PLoS ONE, Vol 11, Iss 2, p e0149000 (2016) |
| ISSN: | 1932-6203 |
| Popis: | BACKGROUND AND PURPOSE:Previous studies of ischemia-reperfusion injury (IRI) in hearts from mice with cardiac-restricted overexpression of CCN2 have shown that CCN2 increases tolerance towards IRI. The objectives of this study were to investigate to what extent post-ischemic administration of recombinant human CCN2 (rhCCN2) would limit infarct size and improve functional recovery and what signaling pathways are involved. EXPERIMENTAL APPROACH:Isolated mice hearts were perfused ad modum Langendorff, subjected to no-flow, global ischemia, and subsequently, exposed to mammalian cell derived, full-length (38-40kDa) rhCCN2 (250 nM) or vehicle during the first 15 min of a 60 min reperfusion period. KEY RESULTS:Post-ischemic administration of rhCCN2 resulted in attenuation of infarct size from 58 ± 4% to 34 ± 2% (p < 0.001) which was abrogated by concomitant administration of the PI3 kinase inhibitor LY294002 (45 ± 3% vs. 50 ± 3%, ns). In congruence with reduction of infarct size rhCCN2 also improved recovery of left ventricular developed pressure (p < 0.05). Western blot analyses of extracts of ex vivo-perfused murine hearts also revealed that rhCCN2 evoked concentration-dependent increase of cardiac phospho-GSK3β (serine-9) contents. CONCLUSIONS AND IMPLICATIONS:We demonstrate that post-ischemic administration of rhCCN2 increases the tolerance of ex vivo-perfused murine hearts to IRI. Mechanistically, this postconditioning effect of rhCCN2 appeared to be mediated by activation of the reperfusion injury salvage kinase pathway as demonstrated by sensitivity to PI3 kinase inhibition and increased CCN2-induced phosphorylation of GSK3β (Ser-9). Thus, the rationale for testing rhCCN2-mediated post-ischemic conditioning of the heart in more complex models is established. |
| Databáze: | OpenAIRE |
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