title: Dichloroacetate prevents restenosis in preclinical animal models of vessel injury.
abstract: Despite the introduction of antiproliferative drug-eluting stents, coronary heart disease remains the leading cause of death in the United States. In-stent restenosis and bypass graft failure are characterized by excessive smooth muscle cell (SMC) proliferation and concomitant myointima formation with luminal obliteration. Here we show that during the development of myointimal hyperplasia in human arteries, SMCs show hyperpolarization of their mitochondrial membrane potential (ΔΨm) and acquire a temporary state with a high proliferative rate and resistance to apoptosis. Pyruvate dehydrogenase kinase isoform 2 (PDK2) was identified as a key regulatory protein, and its activation proved necessary for relevant myointima formation. Pharmacologic PDK2 blockade with dichloroacetate or lentiviral PDK2 knockdown prevented ΔΨm hyperpolarization, facilitated apoptosis and reduced myointima formation in injured human mammary and coronary arteries, rat aortas, rabbit iliac arteries and swine (pig) coronary arteries. In contrast to several commonly used antiproliferative drugs, dichloroacetate did not prevent vessel re-endothelialization. Targeting myointimal ΔΨm and alleviating apoptosis resistance is a novel strategy for the prevention of proliferative vascular diseases.
authors.affiliation: 1] TSI-laboratory, University Heart Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany [2] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany [3] Cardiovascular Surgery, University Heart Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Deuse
authors.affiliation: 1] TSI-laboratory, University Heart Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany [2] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Hua
authors.affiliation: 1] TSI-laboratory, University Heart Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany [2] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Medicine, Atherosclerosis Research Unit, Karolinska Institute, CMM L8:03, 17176 Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Maegdefessel
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Heeren
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Scheja
authors.affiliation: Institute of Functional Biology and Genomics, University of Salamanca-CSIC, Zacarias Gonzalez 2, 37007 Salamanca, Spain.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Bolaños
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Maria-Goeppert-Straße 1, 23562 Lübeck, Germany.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Rakovic
authors.affiliation: Cardiovascular Medicine and Stanford Cardiovascular Institute, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Spin
authors.affiliation: 1] TSI-laboratory, University Heart Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany [2] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Mandy
authors.initials: M
authors.lastname: Stubbendorff
authors.affiliation: Cardiovascular Medicine and Stanford Cardiovascular Institute, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Ikeno
authors.affiliation: Institute of Pathology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Länger
authors.affiliation: 1] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany [2] Department of General and Interventional Cardiology, University Heart Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Zeller
authors.affiliation: 1] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany [2] Department of Anaesthesiology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Leonie
authors.initials: L
authors.lastname: Schulte-Uentrop
authors.affiliation: 1] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany [2] Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Stoehr
authors.affiliation: 1] TSI-laboratory, University Heart Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany [2] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Ryo
authors.initials: R
authors.lastname: Itagaki
authors.affiliation: Cardiovascular Medicine and Stanford Cardiovascular Institute, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.
authors.forename: Francois
authors.initials: F
authors.lastname: Haddad
authors.affiliation: 1] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany [2] Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.affiliation: 1] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany [2] Department of General and Interventional Cardiology, University Heart Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
authors.affiliation: 1] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany [2] Department of Anaesthesiology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Kiefmann
authors.affiliation: 1] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany [2] Cardiovascular Surgery, University Heart Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Reichenspurner
authors.affiliation: Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, Krankenhausstraße 8-10, 91054 Erlangen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Velden
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Maria-Goeppert-Straße 1, 23562 Lübeck, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.affiliation: Cardiovascular Medicine and Stanford Cardiovascular Institute, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Yeung
authors.affiliation: Department of Cardiothoracic Surgery and Stanford Cardiovascular Institute, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Robbins
authors.affiliation: 1] Cardiovascular Medicine and Stanford Cardiovascular Institute, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA [2] Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, California 94304, USA.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Tsao
authors.affiliation: 1] TSI-laboratory, University Heart Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany [2] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany [3] Cardiovascular Surgery, University Heart Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany [4] Department of Cardiothoracic Surgery and Stanford Cardiovascular Institute, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.
authors.forename: Sonja
authors.initials: S
authors.lastname: Schrepfer
mesh_terms: D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000293:injuries* / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D001158:Arteries / Q000187:drug effects / Q000293:injuries* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D003251:Constriction, Pathologic / Q000473:pathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D003999:Dichloroacetic Acid / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D006965:Hyperplasia / Q000188:drug therapy / Q000473:pathology; D007083:Iliac Artery / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D008323:Mammary Arteries / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011817:Rabbits; D051381:Rats; D055502:Secondary Prevention; D015607:Stents / Q000009:adverse effects; D013552:Swine; D017539:Tunica Intima / Q000187:drug effects* / Q000293:injuries / Q000473:pathology*
chemical_list: C000631430:PDK2 protein, human; C000631436:Pdk2 protein, rat; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D003999:Dichloroacetic Acid; D017346:Protein Serine-Threonine Kinases
references.citation: Cancer Cell. 2007 Jan;11(1):37-51
references.pmid: 17222789
references.citation: Nature. 2000 Oct 12;407(6805):770-6
references.pmid: 11048727
references.citation: Can J Physiol Pharmacol. 2005 Aug-Sep;83(8-9):701-15
references.pmid: 16333372
references.citation: Nature. 2005 May 26;435(7041):502-6
references.pmid: 15917810
references.citation: J Biol Chem. 1992 May 5;267(13):8834-9
references.pmid: 1374381
references.citation: Science. 1998 Aug 28;281(5381):1309-12
references.pmid: 9721092
references.citation: J Pathol. 2000 Feb;190(3):300-9
references.pmid: 10685064
references.citation: Nat Med. 2002 Nov;8(11):1249-56
references.pmid: 12411952
references.citation: Nat Med. 2006 Sep;12(9):1075-80
references.pmid: 16892061
references.citation: Nat Med. 1998 Sep;4(9):989-90
references.pmid: 9734376
references.citation: J Biol Chem. 2002 Mar 1;277(9):7610-8
references.pmid: 11751859
references.citation: Circulation. 2009 Jan 27;119(3):480-6
references.pmid: 19171871
references.citation: J Mol Cell Cardiol. 2009 Jun;46(6):821-31
references.pmid: 19265700
references.citation: Biochem J. 2004 Jan 15;377(Pt 2):347-55
references.pmid: 14561215
references.citation: Nat Rev Mol Cell Biol. 2001 Jan;2(1):67-71
references.pmid: 11413468
references.citation: Cell Mol Life Sci. 2007 Apr;64(7-8):830-49
references.pmid: 17310282