title: Inhibition of class I histone deacetylase activity represses matrix metalloproteinase-2 and -9 expression and preserves LV function postmyocardial infarction.
abstract: Left ventricular (LV) remodeling, after myocardial infarction (MI), can result in LV dilation and LV pump dysfunction. Post-MI induction of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, have been implicated as causing deleterious effects on LV and extracellular matrix remodeling in the MI region and within the initially unaffected remote zone. Histone deacetylases (HDACs) are a class of enzymes that affect the transcriptional regulation of genes during pathological conditions. We assessed the efficacy of both class I/IIb- and class I-selective HDAC inhibitors on MMP-2 and MMP-9 abundance and determined if treatment resulted in the attenuation of adverse LV and extracellular matrix remodeling and improved LV pump function post-MI. MI was surgically induced in MMP-9 promoter reporter mice and randomized for treatment with a class I/IIb HDAC inhibitor for 7 days post-MI. After MI, LV dilation, LV pump dysfunction, and activation of the MMP-9 gene promoter were significantly attenuated in mice treated with either the class I/IIb HDAC inhibitor tichostatin A or suberanilohydroxamic acid (voronistat) compared with MI-only mice. Immunohistological staining and zymographic levels of MMP-2 and MMP-9 were reduced with either tichostatin A or suberanilohydroxamic acid treatment. Class I HDAC activity was dramatically increased post-MI. Treatment with the selective class I HDAC inhibitor PD-106 reduced post-MI levels of both MMP-2 and MMP-9 and attenuated LV dilation and LV pump dysfunction post-MI, similar to class I/IIb HDAC inhibition. Taken together, these unique findings demonstrate that selective inhibition of class I HDACs may provide a novel therapeutic means to attenuate adverse LV remodeling post-MI.
authors: Gazes Cardiac Research Institute, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina;
authors: Santhosh K
authors: SK
authors: Mani
authors: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina;
authors: Christine B
authors: CB
authors: Kern
authors: Gazes Cardiac Research Institute, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina;
authors: Denise
authors: D
authors: Kimbrough
authors: Gazes Cardiac Research Institute, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina;
authors: Benjamin
authors: B
authors: Addy
authors: Gazes Cardiac Research Institute, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina;
authors: Harinath
authors: H
authors: Kasiganesan
authors: Department of Surgery, Medical University of South Carolina, Charleston, South Carolina;
authors: William T
authors: WT
authors: Rivers
authors: Department of Surgery, Medical University of South Carolina, Charleston, South Carolina;
authors: Risha K
authors: RK
authors: Patel
authors: Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina;
authors: James C
authors: JC
authors: Chou
authors: Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina.
authors: Francis G
authors: FG
authors: Spinale
authors: Department of Surgery, Medical University of South Carolina, Charleston, South Carolina;
authors: Rupak
authors: R
authors: Mukherjee
authors: Gazes Cardiac Research Institute, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina; Ralph H. Johnson Veterans Affairs Medical Center, Medical University of South Carolina, Charleston, South Carolina; and menickd@musc.edu.
authors: Donald R
authors: DR
authors: Menick
mesh_terms: D000818:Animals; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D056572:Histone Deacetylase Inhibitors; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1
keywords: LV remodeling; histone deacetylase; macrophages; matrix metalloproteinases; myocardial infarction; transcriptional regulation