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

• Published in: Nature communications Vol. 6; no. 1; p. 6656
• Main Authors: Pillai, Vinodkumar B., Samant, Sadhana, Sundaresan, Nagalingam R., Raghuraman, Hariharasundaram, Kim, Gene, Bonner, Michael Y., Arbiser, Jack L., Walker, Douglas I., Jones, Dean P., Gius, David, Gupta, Mahesh P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.04.2015; Nature Publishing Group
• Subjects: 13; 13/2; 13/31; 38; 38/109; 38/77; 42; 631/154/349; 631/443/592/1540; 631/92/612/100/2285; 631/92/612/1240; 96; 96/106; 96/95; Acetylation - drug effects; Adenosine Triphosphatases - antagonists & inhibitors; Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Animals; Biphenyl Compounds - pharmacology; Cardiomegaly - chemically induced; Cardiomegaly - genetics; Cardiomegaly - pathology; Cardiomegaly - prevention & control; Cardiotonic Agents - pharmacology; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Enzyme Activation; Fibroblasts - drug effects; Fibroblasts - enzymology; Fibroblasts - pathology; Gene Expression Regulation; Humanities and Social Sciences; Isoproterenol; Lignans - pharmacology; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mitochondria - drug effects; Mitochondria - enzymology; Mitochondria - pathology; multidisciplinary; Myocardium - enzymology; Myocardium - pathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - enzymology; Myocytes, Cardiac - pathology; Myofibroblasts - drug effects; Myofibroblasts - enzymology; Myofibroblasts - pathology; Phenylephrine - pharmacology; Primary Cell Culture; Reactive Oxygen Species - antagonists & inhibitors; Reactive Oxygen Species - metabolism; Science; Science (multidisciplinary); Signal Transduction; Sirtuin 3 - genetics; Sirtuin 3 - metabolism; Superoxide Dismutase - antagonists & inhibitors; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms7656

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. The chemical honokiol is found in the bark of magnolia trees, which are used for traditional medicine in Asian countries. Here, Pillai et al , show honokiol protects the heart from hypertrophic remodelling in mice, and even reverses established cardiac hypertrophy, by activating the deacetylase Sirt3.