title: Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3.
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.
authors: Departments of Surgery, University of Chicago, Chicago, Illinois, USA.
authors: Vinodkumar B
authors: VB
authors: Pillai
authors: Departments of Surgery, University of Chicago, Chicago, Illinois, USA.
authors: Sadhana
authors: S
authors: Samant
authors: Departments of Surgery, University of Chicago, Chicago, Illinois, USA.
authors: Nagalingam R
authors: NR
authors: Sundaresan
authors: Departments of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA.
authors: Hariharasundaram
authors: H
authors: Raghuraman
authors: Departments of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
authors: Gene
authors: G
authors: Kim
authors: Department of Dermatology, Atlanta Veterans Administration Health Center, Atlanta, Georgia, USA.
authors: Michael Y
authors: MY
authors: Bonner
authors: Department of Dermatology, Atlanta Veterans Administration Health Center, Atlanta, Georgia, USA.
authors: Jack L
authors: JL
authors: Arbiser
authors: Department of Biochemistry and Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Douglas I
authors: DI
authors: Walker
authors: Department of Biochemistry and Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Dean P
authors: DP
authors: Jones
authors: Department of Radiation Oncology, Northwestern University, Chicago, Illinois 60611, USA.
authors: David
authors: D
authors: Gius
authors: Departments of Surgery, University of Chicago, Chicago, Illinois, USA.
authors: Mahesh P
authors: MP
authors: Gupta
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005786:Gene Expression Regulation; D007545:Isoproterenol; D017705:Lignans / Q000494:pharmacology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D025261:Mitochondrial Proton-Translocating ATPases; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D058628:Myofibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010656:Phenylephrine / Q000494:pharmacology; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000251:Adenosine Triphosphatases; D001713:Biphenyl Compounds; D002316:Cardiotonic Agents; D002352:Carrier Proteins; D007545:Isoproterenol; D017705:Lignans; D008565:Membrane Proteins; D025261:Mitochondrial Proton-Translocating ATPases; D010656:Phenylephrine; D017382:Reactive Oxygen Species; D056566:Sirtuin 3; D013482:Superoxide Dismutase; C525046:Sirt3 protein, mouse; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C020439:oligomycin sensitivity-conferring protein