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- Title
Regulation of trehalase expression inhibits apoptosis in diapause Cardioprotective 3',4'-dihydroxyflavonol attenuation of JNK and p38MAPK signalling involves CaMKII inhibition.
- Authors
LIM, Nicholas R.; THOMAS, Colleen J.; SILVA, Lokugan S.; YEAP, Yvonne Y.; YAP, Suwan; BELL, James R.; DELBRIDGE, Lea M. D.; BOGOYEVITCH, Marie A.; WOODMAN, Owen L.; WILLIAMS, Spencer J.; MAY, Clive N.; NG, Dominic C. H.
- Abstract
DiOHF (3',4'-dihydroxyflavonol) is cardioprotective against I/R (ischaemia/reperfusion) injury. The biological activities of flavonols are associated with kinase modulation to alter cell signalling. We thus investigated the effects of DiOHF on the activation of MAPKs (mitogen-activated protein kinases) that regulate the cardiac stress response. In an ovine model of I/R, JNK (c-Jun N-terminal kinase), p38MAPK, ERK (extracellularsignal- regulated kinase) and Akt were activated, and NP202, a pro-drug of DiOHF, reduced infarct size and inhibited JNK and p38MAPK activation, whereas ERK and Akt phosphorylation were unaltered. Similarly, in cultured myoblasts, DiOHF pre-treatment preserved viability and inhibited activation of JNK and p38MAPK, but not ERK in response to acute oxidative and chemotoxic stress. Furthermore, DiOHF prevented stress-activation of the direct upstream regulators MKK4/7 (MAPK kinase 4/7) and MKK3/6 respectively. We utilized small-molecule affinity purification and identified CaMKII (Ca2+ /calmodulin-dependent protein kinase II) as a kinase targeted by DiOHF and demonstrated potent CaMKII inhibition by DiOHF in vitro. Moreover, the specific inhibition of CaMKII with KN-93, but not KN-92, prevented oxidative stress-induced activation of JNK and p38MAPK. The present study indicates DiOHF inhibition of CaMKII and attenuation of MKK3/6 → p38MAPK andMKK4/7 → JNKsignalling as a requirement for the protective effects of DiOHF against stress stimuli and myocardial I/R injury.
- Publication
Biochemical Journal, 2013, Vol 456, Issue 2, p149
- ISSN
0264-6021
- Publication type
Academic Journal
- DOI
10.1042/BJ20121538