Cardioprotective 3',4'-dihydroxyflavonol attenuation of JNK and p38MAPK signalling involves CaMKII inhibition

Lim, N, Thomas, C, Silva, L, Yeap, Y, Yap, S, Bell, J, Delbridge, L, Bogoyevitch, M, Woodman, O, Williams, S, May, C and Ng, D 2013, 'Cardioprotective 3',4'-dihydroxyflavonol attenuation of JNK and p38MAPK signalling involves CaMKII inhibition', Biochemical Journal, vol. 456, no. 2, pp. 149-161.


Document type: Journal Article
Collection: Journal Articles

Title Cardioprotective 3',4'-dihydroxyflavonol attenuation of JNK and p38MAPK signalling involves CaMKII inhibition
Author(s) Lim, N
Thomas, C
Silva, L
Yeap, Y
Yap, S
Bell, J
Delbridge, L
Bogoyevitch, M
Woodman, O
Williams, S
May, C
Ng, D
Year 2013
Journal name Biochemical Journal
Volume number 456
Issue number 2
Start page 149
End page 161
Total pages 13
Publisher Portland Press
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 D101HF 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), p38(MAPK), ERK (extracellular-signal-regulated kinase) and Akt were activated, and NP202, a pro-drug of DiOHF, reduced infarct size and inhibited INK and p38(MAPK) activation, whereas ERK and Akt phosphorylation were unaltered. Similarly, in cultured myoblasts, DiOHF pre-treatment preserved viability and inhibited activation DiOHF and p38(MAPK), 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 INK and p38(MAPK). The present study indicates DiOHF inhibition of CaMKII and attenuation of MKK3/6 -> p38(MAPK) and MKK4/7 -> JNK signalling as a requirement for the protective effects of DiOHF against stress stimuli and myocardial I/R injury.
Subject Basic Pharmacology
Keyword(s) Ca2+ /calmodulin-dependent protein kinase II (CaMKII)
cell stress
flavonol
c-Jun N-terminal kinase (JNK)
kinase
myocardial ischaemia/reperfusion
p38
DOI - identifier 10.1042/BJ20121538
Copyright notice © The Authors Journal compilation © 2013 Biochemical Society
ISSN 0264-6021
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Citation counts: TR Web of Science Citation Count  Cited 13 times in Thomson Reuters Web of Science Article | Citations
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