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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 (??m) 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 ??m 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 ??m and alleviating apoptosis resistance is a novel strategy for the prevention of proliferative vascular diseases.

SUBMITTER: Deuse T

PROVIDER: S-EPMC4323184 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Dichloroacetate prevents restenosis in preclinical animal models of vessel injury.

Deuse Tobias T Hua Xiaoqin X Wang Dong D Maegdefessel Lars L Heeren Joerg J Scheja Ludger L Bolaños Juan P JP Rakovic Aleksandar A Spin Joshua M JM Stubbendorff Mandy M Ikeno Fumiaki F Länger Florian F Zeller Tanja T Schulte-Uentrop Leonie L Stoehr Andrea A Itagaki Ryo R Haddad Francois F Eschenhagen Thomas T Blankenberg Stefan S Kiefmann Rainer R Reichenspurner Hermann H Velden Joachim J Klein Christine C Yeung Alan A Robbins Robert C RC Tsao Philip S PS Schrepfer Sonja S

Nature 20140420 7502

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 ...[more]

PMID: 24747400

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Project description:RationaleChemotherapy-induced cognitive impairment (CICI), chemobrain, and chemofog are the common terms for mental dysfunction in a cancer patient/survivor under the influence of chemotherapeutics. CICI is manifested as short/long term memory problems and delayed mental processing, which interferes with a person's day-to-day activities. Understanding CICI mechanisms help in developing therapeutic interventions that may alleviate the disease condition. Animal models facilitate critical evaluation to elucidate the underlying mechanisms and form an integral part of verifying different treatment hypotheses and strategies.ObjectivesA methodical evaluation of scientific literature is required to understand cognitive changes associated with the use of chemotherapeutic agents in different preclinical studies. This review mainly emphasizes animal models developed with various chemotherapeutic agents individually and in combination, with their proposed mechanisms contributing to the cognitive dysfunction. This review also points toward the analysis of chemobrain in healthy animals to understand the mechanism of interventions in absence of tumor and in tumor-bearing animals to mimic human cancer conditions to screen potential drug candidates against chemobrain.ResultsSubstantial memory deficit as a result of commonly used chemotherapeutic agents was evidenced in healthy and tumor-bearing animals. Spatial and episodic cognitive impairments, alterations in neurotrophins, oxidative and inflammatory markers, and changes in long-term potentiation were commonly observed changes in different animal models irrespective of the chemotherapeutic agent.ConclusionDyscognition exists as one of the serious side effects of cancer chemotherapy. Due to differing mechanisms of chemotherapeutic agents with differing tendencies to alter behavioral and biochemical parameters, chemotherapy may present a significant risk in resulting memory impairments in healthy as well as tumor-bearing animals.

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Dichloroacetate prevents restenosis in preclinical animal models of vessel injury.

Publications

Dichloroacetate prevents restenosis in preclinical animal models of vessel injury.

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