This Article Full Text Full Text (PDF) All Versions of this Article: 119/12/1643    most recent CIRCULATIONAHA.108.787440v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dolinsky, V. W. Articles by Dyck, J. R.B. Search for Related Content PubMed PubMed Citation Articles by Dolinsky, V. W. Articles by Dyck, J. R.B. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Other myocardial biology Animal models of human disease Cell signalling/signal transduction Hypertrophy

(Circulation. 2009;119:1643-1652.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

Resveratrol Prevents the Prohypertrophic Effects of Oxidative Stress on LKB1

Vernon W. Dolinsky, PhD; Anita Y.M. Chan, BSc; Isabelle Robillard Frayne, MSc; Peter E. Light, PhD; Christine Des Rosiers, PhD; Jason R.B. Dyck, PhD

From the Cardiovascular Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta (V.W.D., A.Y.M.C., P.E.L., J.R.B.D.), and Montreal Heart Institute and University of Montreal, Montreal, Quebec (I.R.F., C.D.R.), Canada.

Correspondence to Dr Jason R.B. Dyck, 458 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. E-mail jason.dyck{at}ualberta.ca

Received May 2, 2008; accepted January 23, 2009.

Background— Master regulators of protein synthesis such as mammalian target of rapamycin (mTOR) and p70S6 kinase contribute to left ventricular hypertrophy. These prohypertrophic pathways are modulated by a number of kinase cascades, including the hierarchical LKB1/AMP-activated protein kinase (AMPK) energy-sensing pathway. Because oxidative stress inhibits the LKB1/AMPK signaling axis to promote abnormal cell growth in cancer cells, we investigated whether oxidative stress associated with hypertension also results in the inhibition of this kinase circuit to contribute to left ventricular hypertrophy.

Methods and Results— In the spontaneously hypertensive rat, a well-established genetic model of hypertension and subsequent cardiac hypertrophy, the development of left ventricular hypertrophy is associated with an increase in the electrophilic lipid peroxidation byproduct 4-hydroxy-2-nonenal (HNE). Using isolated cardiomyocytes, we show that elevated levels of HNE result in the formation of HNE-LKB1 adducts that inhibit LKB1 and subsequent AMPK activity. Consistent with inhibition of the LKB1/AMPK signaling pathway, the mTOR/p70S6 kinase system is activated, which is permissive for cardiac myocyte cell growth. Treatment of cardiomyocytes with resveratrol prevents HNE modification of the LKB1/AMPK signaling axis and blunts the prohypertrophic p70S6 kinase response. Furthermore, administration of resveratrol to spontaneously hypertensive rats results in increased AMPK phosphorylation and activity and reduced left ventricular hypertrophy.

Conclusions— Our data identify a molecular mechanism in the cardiomyocyte involving the oxidative stress–derived lipid peroxidation byproduct HNE and the LKB1/AMPK signaling pathway that contributes to the development of left ventricular hypertrophy. We also suggest that resveratrol may be a potential therapy for patients at risk for developing pathological cardiac hypertrophy by preventing this prohypertrophic process.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				K. D. Folmes, A. Y.M. Chan, D. P.Y. Koonen, T. C. Pulinilkunnil, I. Baczko, B. E. Hunter, S. Thorn, M. F. Allard, R. Roberts, M. H. Gollob, et al. Distinct Early Signaling Events Resulting From the Expression of the PRKAG2 R302Q Mutant of AMPK Contribute to Increased Myocardial Glycogen Circ Cardiovasc Genet, October 1, 2009; 2(5): 457 - 466. [Abstract] [Full Text] [PDF]

				Q. Li, J. Li, and J. Ren UCF-101 mitigates streptozotocin-induced cardiomyocyte dysfunction: role of AMPK Am J Physiol Endocrinol Metab, October 1, 2009; 297(4): E965 - E973. [Abstract] [Full Text] [PDF]

				Q. Li, L. K. Hueckstaedt, and J. Ren The protease inhibitor UCF-101 ameliorates streptozotocin-induced mouse cardiomyocyte contractile dysfunction in vitro: role of AMP-activated protein kinase Exp Physiol, September 1, 2009; 94(9): 984 - 994. [Abstract] [Full Text] [PDF]

				Z. Xie, Y. Dong, J. Zhang, R. Scholz, D. Neumann, and M.-H. Zou Identification of the Serine 307 of LKB1 as a Novel Phosphorylation Site Essential for Its Nucleocytoplasmic Transport and Endothelial Cell Angiogenesis Mol. Cell. Biol., July 1, 2009; 29(13): 3582 - 3596. [Abstract] [Full Text] [PDF]