Involvement of microtubules in the tolerance of cardiomyocytes to cold ischemia-reperfusion |
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Authors: | Lisa Devillard David Vandroux Cindy Tissier Laure Dumont Jessica Borgeot Luc Rochette Pierre Athias |
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Institution: | (1) Laboratory of Experimental Cardiovascular Physiopathology and Pharmacology, IFR Santé-STIC, Institute of Cardiovascular Research, University Hospital Center, P.B. 77908, 21079 Dijon Cedex, France |
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Abstract: | Before transplantation, the heart graft is preserved by the use of cold storage in order to limit ischemia-reperfusion stress.
However, sustained exposure to low temperature may induce myocardial ultrastructural damage, particularly microtubules (MT)
disruption. Previous data suggested that tubulin-binding agents are able to attenuate cold-induced cytoskeleton alterations.
Thus, the aim of the present work was to study the influence of docetaxel (DX, a tubulin-binding taxane) on the effects of
deep hypothermia (4°C) and of simulated cold ischemia-reperfusion on the MT network and oxidative stress of cardiomyocyte
(CM) in monolayer cultures prepared from newborn rat ventricles. The MT network was explored by immunocytochemistry and Western-blotting,
the cell stress by tetrazolium dye assay (MTT) and lactate dehydrogenase (LDH) release, and the superoxide production by the
dihydroethidium probe (DHE). The MT assembly remained stable after 4 and 8 h of hypothermia. Tubulin acetylation was promoted
in CM subjected to 4-h hypothermia. Low temperature reduced the mitochondrial function and increased the basal LDH release.
The cold ischemia during 4 and 8 h preserved MT network. Docetaxel promoted MT polymerization and tubulin acetylation in basal
and in cold conditions. This drug decreased the release of LDH induced by cold ischemia. Moreover, hypothermia (4 h) significantly
raised the anion superoxide production. Docetaxel decreased this oxidative stress in the control CM and in CM submitted to
4 h of hypothermia. These data demonstrated that stabilizing MT with DX exerted a protective effect on CM subjected to hypothermia
and to cold ischemia-reperfusion. Tubulin-ligands should be thus considered to improve the tolerance of the heart graft toward
stressing conservative conditions. |
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Keywords: | Cardiomyocytes Neonatal rats Microtubules Hypothermia Simulated ischemia-reperfusion Oxidative stress Docetaxel |
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