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Nature. 2014 May 29;509(7502):641-4. doi: 10.1038/nature13232. Epub 2014 Apr 20.

Dichloroacetate prevents restenosis in preclinical animal models of vessel injury.

Author information

1
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.
2
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
Department of Medicine, Atherosclerosis Research Unit, Karolinska Institute, CMM L8:03, 17176 Stockholm, Sweden.
4
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
5
Institute of Functional Biology and Genomics, University of Salamanca-CSIC, Zacarias Gonzalez 2, 37007 Salamanca, Spain.
6
Institute of Neurogenetics, University of Lübeck, Maria-Goeppert-Straße 1, 23562 Lübeck, Germany.
7
Cardiovascular Medicine and Stanford Cardiovascular Institute, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.
8
Institute of Pathology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
9
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.
10
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.
11
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.
12
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.
13
Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, Krankenhausstraße 8-10, 91054 Erlangen, Germany.
14
Department of Cardiothoracic Surgery and Stanford Cardiovascular Institute, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.
15
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.
16
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.

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.

PMID:
24747400
PMCID:
PMC4323184
DOI:
10.1038/nature13232
[Indexed for MEDLINE]
Free PMC Article

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