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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, Vol. 509, No. 7502, 29.05.2014, p. 641-644.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Deuse, T, Hua, X, Wang, D, Maegdefessel, L, Heeren, J, Scheja, L, Bolaños, JP, Rakovic, A, Spin, JM, Stubbendorff, M, Ikeno, F, Länger, F, Zeller, T, Schulte-Uentrop, L, Stoehr, A, Itagaki, R, Haddad, F, Eschenhagen, T, Blankenberg, S, Kiefmann, R, Reichenspurner, H, Velden, J, Klein, C, Yeung, A, Robbins, RC, Tsao, PS & Schrepfer, S 2014, 'Dichloroacetate prevents restenosis in preclinical animal models of vessel injury', NATURE, vol. 509, no. 7502, pp. 641-644. https://doi.org/10.1038/nature13232

APA

Deuse, T., Hua, X., Wang, D., Maegdefessel, L., Heeren, J., Scheja, L., Bolaños, J. P., Rakovic, A., Spin, J. M., Stubbendorff, M., Ikeno, F., Länger, F., Zeller, T., Schulte-Uentrop, L., Stoehr, A., Itagaki, R., Haddad, F., Eschenhagen, T., Blankenberg, S., ... Schrepfer, S. (2014). Dichloroacetate prevents restenosis in preclinical animal models of vessel injury. NATURE, 509(7502), 641-644. https://doi.org/10.1038/nature13232

Vancouver

Deuse T, Hua X, Wang D, Maegdefessel L, Heeren J, Scheja L et al. Dichloroacetate prevents restenosis in preclinical animal models of vessel injury. NATURE. 2014 May 29;509(7502):641-644. https://doi.org/10.1038/nature13232

Bibtex

@article{380c2983b06046d0a3291d222d021511,
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.",
author = "Tobias Deuse and Xiaoqin Hua and Dong Wang and Lars Maegdefessel and Joerg Heeren and Ludger Scheja and Bola{\~n}os, {Juan P} and Aleksandar Rakovic and Spin, {Joshua M} and Mandy Stubbendorff and Fumiaki Ikeno and Florian L{\"a}nger and Tanja Zeller and Leonie Schulte-Uentrop and Andrea Stoehr and Ryo Itagaki and Francois Haddad and Thomas Eschenhagen and Stefan Blankenberg and Rainer Kiefmann and Hermann Reichenspurner and Joachim Velden and Christine Klein and Alan Yeung and Robbins, {Robert C} and Tsao, {Philip S} and Sonja Schrepfer",
year = "2014",
month = may,
day = "29",
doi = "10.1038/nature13232",
language = "English",
volume = "509",
pages = "641--644",
journal = "NATURE",
issn = "0028-0836",
publisher = "NATURE PUBLISHING GROUP",
number = "7502",

}

RIS

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 -