Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3

Vinodkumar B. Pillai, Sadhana Samant, Nagalingam R. Sundaresan, Hariharasundaram Raghuraman, Gene Kim, Michael Y. Bonner, Jack L. Arbiser, Douglas I. Walker, Dean P. Jones, David Gius, Mahesh P. Gupta*

*Corresponding author for this work

Research output: Contribution to journalArticle

167 Scopus citations

Abstract

Honokiol (HKL) is a natural biphenolic compound derived from the bark of magnolia trees with anti-inflammatory, anti-oxidative, anti-tumour and neuroprotective properties. Here we show that HKL blocks agonist-induced and pressure overload-mediated, cardiac hypertrophic responses, and ameliorates pre-existing cardiac hypertrophy, in mice. Our data suggest that the anti-hypertrophic effects of HKL depend on activation of the deacetylase Sirt3. We demonstrate that HKL is present in mitochondria, enhances Sirt3 expression nearly twofold and suggest that HKL may bind to Sirt3 to further increase its activity. Increased Sirt3 activity is associated with reduced acetylation of mitochondrial Sirt3 substrates, MnSOD and oligomycin-sensitivity conferring protein (OSCP). HKL-treatment increases mitochondrial rate of oxygen consumption and reduces ROS synthesis in wild type, but not in Sirt3-KO cells. Moreover, HKL-treatment blocks cardiac fibroblast proliferation and differentiation to myofibroblasts in a Sirt3-dependent manner. These results suggest that HKL is a pharmacological activator of Sirt3 capable of blocking, and even reversing, the cardiac hypertrophic response.

Original languageEnglish (US)
Article number6656
JournalNature communications
Volume6
DOIs
StatePublished - Apr 14 2015

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Pillai, V. B., Samant, S., Sundaresan, N. R., Raghuraman, H., Kim, G., Bonner, M. Y., Arbiser, J. L., Walker, D. I., Jones, D. P., Gius, D., & Gupta, M. P. (2015). Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3. Nature communications, 6, [6656]. https://doi.org/10.1038/ncomms7656