Resveratrol prevents the prohypertrophic effects of oxidative stress on LKB1.
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.


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.
Dolinsky
Vernon W
VW
Cardiovascular Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2S2, Canada.
Chan
Anita Y M
AY
Robillard Frayne
Isabelle
I
Light
Peter E
PE
Des Rosiers
Christine
C
Dyck
Jason R B
JR
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000447:Aldehydes / Q000032:analysis; D000818:Animals; D006332:Cardiomegaly / Q000517:prevention & control; D002478:Cells, Cultured; D006973:Hypertension / Q000150:complications; D017379:Hypertrophy, Left Ventricular / Q000517:prevention & control*; D015227:Lipid Peroxidation; D032383:Myocytes, Cardiac; D018384:Oxidative Stress / Q000187:drug effects*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D011918:Rats, Inbred SHR; D000077185:Resveratrol; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
D000447:Aldehydes; D013267:Stilbenes; D011494:Protein Kinases; C546845:mTOR protein, rat; D017346:Protein Serine-Threonine Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C488755:Stk11 protein, rat; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; C027576:4-hydroxy-2-nonenal; D000077185:Resveratrol