Dichloroacetate prevents restenosis in preclinical animal models of vessel injury
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Dichloroacetate prevents restenosis in preclinical animal models of vessel injury. / Deuse, Tobias; Hua, Xiaoqin; Wang, Dong; Maegdefessel, Lars; Heeren, Joerg; Scheja, Ludger; Bolaños, Juan P; Rakovic, Aleksandar; Spin, Joshua M; Stubbendorff, Mandy; Ikeno, Fumiaki; Länger, Florian; Zeller, Tanja; Schulte-Uentrop, Leonie; Stoehr, Andrea; Itagaki, Ryo; Haddad, Francois; Eschenhagen, Thomas; Blankenberg, Stefan; Kiefmann, Rainer; Reichenspurner, Hermann; Velden, Joachim; Klein, Christine; Yeung, Alan; Robbins, Robert C; Tsao, Philip S; Schrepfer, Sonja.
in: NATURE, Jahrgang 509, Nr. 7502, 29.05.2014, S. 641-644.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Dichloroacetate prevents restenosis in preclinical animal models of vessel injury
AU - Deuse, Tobias
AU - Hua, Xiaoqin
AU - Wang, Dong
AU - Maegdefessel, Lars
AU - Heeren, Joerg
AU - Scheja, Ludger
AU - Bolaños, Juan P
AU - Rakovic, Aleksandar
AU - Spin, Joshua M
AU - Stubbendorff, Mandy
AU - Ikeno, Fumiaki
AU - Länger, Florian
AU - Zeller, Tanja
AU - Schulte-Uentrop, Leonie
AU - Stoehr, Andrea
AU - Itagaki, Ryo
AU - Haddad, Francois
AU - Eschenhagen, Thomas
AU - Blankenberg, Stefan
AU - Kiefmann, Rainer
AU - Reichenspurner, Hermann
AU - Velden, Joachim
AU - Klein, Christine
AU - Yeung, Alan
AU - Robbins, Robert C
AU - Tsao, Philip S
AU - Schrepfer, Sonja
PY - 2014/5/29
Y1 - 2014/5/29
N2 - 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.
AB - 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.
U2 - 10.1038/nature13232
DO - 10.1038/nature13232
M3 - SCORING: Journal article
C2 - 24747400
VL - 509
SP - 641
EP - 644
JO - NATURE
JF - NATURE
SN - 0028-0836
IS - 7502
ER -