論文 - 詳細
| RRC ID | 27889 |
|---|---|
| 著者 | Zhai P, Sciarretta S, Galeotti J, Volpe M, Sadoshima J. |
| タイトル | Differential roles of GSK-3β during myocardial ischemia and ischemia/reperfusion. |
| ジャーナル | Circ Res |
| Abstract |
RATIONALE:Inhibition of glycogen synthase kinase-3 (GSK-3) protects the heart during ischemia/reperfusion (I/R), yet the underlying mechanisms of cardioprotection afforded by beta isoform-specific inhibition GSK-3 remain to be elucidated. OBJECTIVE:We studied the molecular mechanism mediating the effect of GSK-3β activation/inhibition upon myocardial injury during prolonged ischemia and I/R. METHODS AND RESULTS:Beta isoform-specific inhibition of GSK-3 by dominant negative GSK-3β in transgenic mice (Tg-DnGSK-3β) or in heterozygous GSK-3β knock-out mice (GSK-3β+/-) significantly increased, whereas activation of GSK-3β in constitutively active GSK-3β knock-in mice (βKI) significantly decreased, myocardial ischemic injury after prolonged ischemia. In contrast, inhibition of GSK-3β in Tg-DnGSK-3β or GSK-3β+/- significantly reduced, while activation of GSK-3β in βKI significantly enhanced, myocardial I/R injury. Inhibition of GSK-3β stimulated mTOR signaling and inhibited autophagy through a rapamycin-sensitive (mTOR dependent) mechanism. Rapamycin enhanced autophagy and, at the same time, abolished the effects of GSK-3β inhibition on both prolonged ischemic injury and I/R injury. Importantly, the influence of rapamycin over the effects of GSK-3β inhibition on myocardial injury was reversed by inhibition of autophagy. CONCLUSIONS:Our results suggest that beta isoform-specific inhibition of GSK-3 exacerbates ischemic injury but protects against I/R injury by modulating mTOR and autophagy. |
| 巻・号 | 109(5) |
| ページ | 502-11 |
| 公開日 | 2011-8-19 |
| DOI | 10.1161/CIRCRESAHA.111.249532 |
| PII | CIRCRESAHA.111.249532 |
| PMID | 21737790 |
| PMC | PMC3158807 |
| MeSH | Animals Autophagy / genetics Gene Knock-In Techniques / methods Glycogen Synthase Kinase 3 / genetics Glycogen Synthase Kinase 3 / physiology* Glycogen Synthase Kinase 3 beta Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Myocardial Ischemia / enzymology* Myocardial Ischemia / pathology Myocardial Reperfusion Injury / enzymology* Myocardial Reperfusion Injury / pathology Signal Transduction / genetics TOR Serine-Threonine Kinases / genetics TOR Serine-Threonine Kinases / metabolism TOR Serine-Threonine Kinases / physiology |
| IF | 14.467 |
| 引用数 | 114 |
| WOS 分野 | CARDIAC & CARDIOVASCULAR SYSTEMS HEMATOLOGY PERIPHERAL VASCULAR DISEASE |
| リソース情報 | |
| 実験動物マウス | RBRC00806 |