Resveratrol prevents pathological but not physiological cardiac hypertrophy

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2015-04, Vol.93 (4), p.413-425
• Main Authors: Dolinsky, Vernon W., Soltys, Carrie-Lynn M., Rogan, Kyle J., Chan, Anita Y. M., Nagendran, Jeevan, Wang, Shaohua, Dyck, Jason R. B.
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - metabolism; Animals; Antioxidants - pharmacology; Biomedical and Life Sciences; Biomedicine; Cells, Cultured; Exercise; Heart Ventricles - drug effects; Heart Ventricles - metabolism; Heart Ventricles - pathology; Human Genetics; Humans; Hypertrophy, Left Ventricular - metabolism; Hypertrophy, Left Ventricular - pathology; Hypertrophy, Left Ventricular - prevention & control; Insulin-Like Growth Factor I - metabolism; Internal Medicine; Mice, Inbred C57BL; Molecular Medicine; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; NFATC Transcription Factors - metabolism; Original Article; Rats; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Signal Transduction - drug effects; Stilbenes - pharmacology; Transcriptional Activation - drug effects; Ventricular Function - drug effects
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-014-1220-8

The mechanisms responsible for how resveratrol inhibits pathological left ventricular hypertrophy (LVH) but not physiological LVH have not been elucidated. Herein, we show that in rat cardiomyocytes, lower concentrations of resveratrol (0.1 and 1 μM) are efficient at selectively inhibiting important regulators involved in pathological LVH (such as nuclear factor of activated T cells (NFAT)) while not affecting pathways involved in physiological LVH (Akt and p70S6 kinase (p70S6K)). These differential responses are also observed in both mouse and rat models of in vivo physiological and pathological LVH. Interestingly, in all of the experiments involving a low concentration of resveratrol (1 μM), the observed effects on Akt, p70S6K, and NFAT were independent from AMP-activated protein kinase (AMPK) activation while these effects at higher concentrations of resveratrol (50 μM) were potentiated by AMPK activation. In summary, we show that resveratrol can concentration/dose selectively inhibit various pro-hypertrophic signaling pathways and that resveratrol has differential effects on the modification of these signaling cascades in response to pathological stimuli versus physiological stimuli. This has important clinical implications as our findings support the concept that resveratrol may be useful in the selective treatment of pathological LVH. Key message Resveratrol differentially regulates pathological and physiological cardiac hypertrophy. Resveratrol dose selectively inhibits pathological cardiac signaling pathways. Resveratrol inhibits NFAT-dependent transcription. At low concentrations, effects of resveratrol are AMPK-independent. Resveratrol may be used to selectively treat pathological cardiac hypertrophy.