Resveratrol Prevents the Prohypertrophic Effects of Oxidative Stress on LKB1

Abstract

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.

LKB1/AMPK pathway mediates resistin-induced cardiomyocyte hypertrophy in H9c2 embryonic rat cardiomyocytes

“…It has been shown previously that 4-hydroxy-trans-2-nonenal (HNE) and miR-451 promote cardiac hypertrophy through suppression of the LKB1/AMPK pathway (37,38). By contrast, resveratrol or NAD prevents cardiac hypertrophy through enhancing the LKB1/AMPK signal transduction pathway (31,39,40). The current study demonstrates that resistin decreases phosphorylation of LKB1, and subsequently decreases phosphorylation of AMPK.…”

“…LKB1 can phosphorylate downstream AMPK at threonine 172 (30)(31)(32). Metformin, phenformin and AICAR are activators of AMPK (4,(33)(34)(35).…”

Cardiac-specific Deletion of LKB1 Leads to Hypertrophy and Dysfunction

“…Loss of LKB1 resulted in reduced AMPK activity and a corresponding activation of signaling pathways that are major regulators of protein synthesis, namely mTOR, p70S6 kinase, and eEF2 (48). Inhibition of LKB1/AMPK signaling and a subsequent activation of the mTOR/ p70S6 kinase signaling axis have been proposed to create a permissive environment that promotes hypertrophic growth (15). Consistent with this notion, the mTOR/ P70S6 kinase/eEF2 signaling cascade is activated in hearts from LKB1-KO mice, which may contribute to atrial and ventricular hypertrophy in these mice.…”

“…Furthermore, the systemic consequences of LKB1 ablation in skeletal muscle of this strain could conceivably confound the cardiac phenotype especially given the fact that muscle fuel metabolism is altered in these mice (4). Because the role of LKB1 in the cardiac myocyte has been shown to involve the regulation of signaling molecules involved in protein synthesis and cell growth (9) as well as oxidative stress-induced hypertrophy (15), we explored the importance of LKB1 in controlling these prohypertrophic pathways by generating cardiac-specific LKB1 knock-out mice by crossing LKB1…”

Beneficial Effects of Grape Resveratrol on Serum Adiponectin and Inflammation: Clinical Trial in Patients with Stable Coronary Artery Disease

“…Resveratrol is a polyphenolic flavonoid with phytoalexin properties and has several pleotropic effects on cardiovascular function such as anti-oxidant and antiinflammatory effects and metabolic modulation (Fig. 1) [10][11][12][13][14]. However, these studies were performed in animal models and clinical evidence of the therapeutic effectiveness of resveratrol in humans is limited.…”