| Autor: |
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. |
| Předmět: |
|
| Zdroj: |
Biochemical Journal; 12/1/2013, Vol. 456 Issue 2, following p149-161, 15p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
