IJPPP Copyright © 2009-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Int J Physiol Pathophysiol Pharmacol 2009;1(2):116-126.

Original Article
A novel AMPK activator from Chinese herb medicine and ischemia phosphorylate
the cardiac transcription factor FOXO3

Jingying Wang, Heng Ma, Xiaoyu Zhang, Leilei He, Jianming Wu, Xiaoping Gao, Jun Ren, Ji Li

Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, School of
Pharmacy, Laramie, WY 82071; Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, P.R.
China; Department of Research & Development, Kanghong Pharmaceutical Co. Ltd, Chengdu 610000, P.R. China

Received March 10, 2009; accepted March 16, 2009; available online March 25, 2009

Abstract: Oleanolic Acid (OA) is a nature product extracted from Chinese Herb Medicine which is traditionally used as treatment of
diabetes and ischemic heart diseases. Mounting evidence showed that AMP-activated protein kinase (AMPK) has cardioprotective
effect against ischemic injury and the forkhead transcription factor 3 (FOXO3) was recently identified as a downstream target of AMPK.
We hypothesize that OA may protect against ischemic dysfunction of cardiomyocytes via activation of AMPK signaling pathway. Male
C57BL/6 mice which were subjected to in vivo regional cardiac ischemia stimulated AMPK Thr172 phosphorylation, as well as
phosphorylation of downstream FOXO3 (Ser413) and acetyl CoA carboxylase (ACC). The natural product, OA, significantly stimulated
cardiac AMPK activation in cardiomyocyes in time- and dose-dependent manners. The mechanism of AMPK activation by OA may be
due to the loss mitochondrial membrane potential (ΔΨm) as shown by JC-1 fluorescence assay. Intriguingly, OA as an AMPK activator
also triggered FOXO3 (Ser413) phosphorylation in cardiomyocytes. Furthermore, OA treatment can protect cardiomyocytes from
contractile dysfunction induced by hypoxia. Taken together, the results indicated that both ischemia and OA stimulated cardiac AMPK
phosphorylation, as well downstream FOXO3 phosphorylation. The cardioprotective effect of OA maybe associated with activation of
AMPK signaling pathways. (IJPPP903002).

Key words: AMP-activated protein kinase (AMPK), ischemia, Forkhead transcription factor 3 (FOXO3), Oleanolic Acid (OA)

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Address all correspondence to:
Ji Li, PhD
Division of Pharmaceutical Sciences
University of Wyoming, School of Pharmacy
Laramie, WY 82071, USA
Tel: 307-766-6172, Fax: 307-766-2953