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 (extracellular-signal-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 and MKK4/7→JNK signalling as a requirement for the protective effects of DiOHF against stress stimuli and myocardial I/R injury.
Skip Nav Destination
Follow us on Twitter @Biochem_Journal
Article navigation
December 2013
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
Research Article|
November 08 2013
Cardioprotective 3′,4′-dihydroxyflavonol attenuation of JNK and p38MAPK signalling involves CaMKII inhibition
Nicholas R. Lim;
Nicholas R. Lim
1
*Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, VIC 3010, Australia
Search for other works by this author on:
Colleen J. Thomas;
Colleen J. Thomas
1
†Department of Human Biosciences, LaTrobe University, Bundoora, VIC 3086, Australia
‡Florey Institute of Neuroscience and Mental Health, University of Melbourne, Gate 11, Royal Parade, Parkville, VIC 3010, Australia
Search for other works by this author on:
Lokugan S. Silva;
Lokugan S. Silva
*Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, VIC 3010, Australia
Search for other works by this author on:
Yvonne Y. Yeap;
Yvonne Y. Yeap
*Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, VIC 3010, Australia
Search for other works by this author on:
Suwan Yap;
Suwan Yap
§School of Chemistry, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, VIC 3010, Australia
Search for other works by this author on:
James R. Bell;
James R. Bell
∥Department of Physiology, University of Melbourne, Grattan Street, Parkville, VIC 3010, Australia
Search for other works by this author on:
Lea M. D. Delbridge;
Lea M. D. Delbridge
∥Department of Physiology, University of Melbourne, Grattan Street, Parkville, VIC 3010, Australia
Search for other works by this author on:
Marie A. Bogoyevitch;
Marie A. Bogoyevitch
*Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, VIC 3010, Australia
Search for other works by this author on:
Owen L. Woodman;
Owen L. Woodman
¶School of Medical Sciences, Health Innovations Research Institute, RMIT University, PO Box 71, Bundoora, VIC 3083, Australia
Search for other works by this author on:
Spencer J. Williams;
Spencer J. Williams
§School of Chemistry, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, VIC 3010, Australia
Search for other works by this author on:
Clive N. May;
Clive N. May
‡Florey Institute of Neuroscience and Mental Health, University of Melbourne, Gate 11, Royal Parade, Parkville, VIC 3010, Australia
Search for other works by this author on:
Dominic C. H. Ng
Dominic C. H. Ng
2
*Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, VIC 3010, Australia
2To whom correspondence should be addressed (email [email protected]).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
October 08 2012
Revision Received:
August 21 2013
Accepted:
September 16 2013
Accepted Manuscript online:
September 16 2013
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 456 (2): 149–161.
Article history
Received:
October 08 2012
Revision Received:
August 21 2013
Accepted:
September 16 2013
Accepted Manuscript online:
September 16 2013
Citation
Nicholas R. Lim, Colleen J. Thomas, Lokugan S. Silva, Yvonne Y. Yeap, Suwan Yap, James R. Bell, Lea M. D. Delbridge, Marie A. Bogoyevitch, Owen L. Woodman, Spencer J. Williams, Clive N. May, Dominic C. H. Ng; Cardioprotective 3′,4′-dihydroxyflavonol attenuation of JNK and p38MAPK signalling involves CaMKII inhibition. Biochem J 1 December 2013; 456 (2): 149–161. doi: https://doi.org/10.1042/BJ20121538
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Biochemical Society Member Sign in
Sign InSign in via your Institution
Sign in via your InstitutionGet Access To This Article
Follow us on Twitter @Biochem_Journal
Open Access for all
We offer compliant routes for all authors from 2025. With library support, there will be no author nor reader charges in 5 journals. Check here |
![]() View past webinars > |