Uncoupled eNOS annihilates neuregulin-1β-induced cardioprotection: a novel mechanism in pharmacological postconditioning in myocardial infarction
| Autor: | Rüdiger C. Braun-Dullaeus, Stefan Lange, Carsten Wunderlich, Clementine Wischniowski, Gregor Simonis, Ruth H. Strasser, Thomas Eckert, Christof Weinbrenner, Bernd Ebner, Annette Ebner |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Male
Cardiotonic Agents Nitric Oxide Synthase Type III Neuregulin-1 Clinical Biochemistry Myocardial Infarction Blood Pressure Myocardial Reperfusion Injury Pharmacology In Vitro Techniques Arginine Glycogen Synthase Kinase 3 Mice Enos Medicine Animals Cardioprotective Agent Molecular Biology GSK3B Protein kinase B chemistry.chemical_classification Cardioprotection Mice Knockout Reactive oxygen species Glycogen Synthase Kinase 3 beta biology business.industry Cell Biology General Medicine biology.organism_classification Enzyme Activation Mice Inbred C57BL chemistry Anesthesia Phosphorylation Signal transduction business Reactive Oxygen Species Signal Transduction |
| Zdroj: | Molecular and cellular biochemistry. 373(1-2) |
| ISSN: | 1573-4919 |
| Popis: | Myocardial infarct size can be limited by pharmacological postconditioning (pPC) with cardioprotective agents. Cardioprotective effects of neuregulin-1β (NRG) via activation of protein kinase B (Akt) and downstream pathways like endothelial nitric oxide synthase (eNOS) have been postulated based on results from cell culture experiments. The purpose of this study was to investigate if eNOS may be involved in pPC with NRG. NRG application in an ex vivo mouse model (C57Bl6) of ischemia-reperfusion injury was analyzed. Unexpectedly, the infarct size increased when NRG was infused starting 5 min prior to reperfusion, even though protective Akt and GSK3β phosphorylation were enhanced. In eNOS deficient mice, however, NRG significantly reduced the infarct size. Co-infusion of NRG and L-arginine (Arg) lead to a reduction in infarct size in wild type animals. Electron paramagnetic resonance measurements revealed that NRG treatment prior to reperfusion leads to an enhanced release of reactive oxygen species compared to controls and this effect is blunted by co-infusion of Arg. This study documents the cardioprotective mechanisms of NRG signaling to be mediated by GSK3β inactivation. This is the first study to show that this protection fails in situations with dysfunctional eNOS. In eNOS deficient mice NRG exerts its protective effect via the GSK3β pathway, suggesting that the eNOS can limit cardioprotection. As dysfunctional eNOS has been described in cardiovascular risk factors like diabetes, hypertension, and hypercholesterolemia these findings can help to explain lack of postconditioning performance in models of cardiovascular co-morbidities. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink