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dc.contributor.authorPushparaj, Charumathi
dc.contributor.authorDas, Arindam
dc.contributor.authorPurroy, Rosa
dc.contributor.authorNàger Grifo, Mireia
dc.contributor.authorHerreros Danés, Judit
dc.contributor.authorPamplona Gras, Reinald
dc.contributor.authorCantí Nicolás, Carles
dc.date.accessioned2017-01-20T11:12:08Z
dc.date.issued2015
dc.identifier.issn0829-8211
dc.identifier.urihttp://hdl.handle.net/10459.1/59062
dc.description.abstractVoltage-gated calcium channel blockers are widely used for the management of cardiovascular diseases, however little is known about their effects on cardiac cells in vitro. We challenged neonatal ventricular cardiomyocytes (CMs) with therapeutic L-type and T-type Ca2+ channel blockers (nifedipine and mibefradil, respectively), and measured their effects on cell stress and survival, using fluorescent microscopy, Q-PCR and Western blot. Both nifedipine and mibefradil induced a low-level and partially transient up-regulation of three key mediators of the Unfolded Protein Response (UPR), indicative of endoplasmic (ER) reticulum stress. Furthermore, nifedipine triggered the activation of macroautophagy, as evidenced by increased lipidation of microtubule-associated protein 1 light chain 3 (LC3), decreased levels of polyubiquitin-binding protein p62/SQSTM1 and ubiquitinated protein aggregates, that was followed by cell death. In contrast, mibefradil inhibited CMs constitutive macroautophagy and did not promote cell death. The siRNA-mediated gene silencing approach confirmed the pharmacological findings for T-type channels. We conclude that L-type and T-type Ca2+ channel blockers induce ER stress, which is divergently transduced into macroautophagy induction and inhibition, respectively, with relevance for cell viability. Our work identifies VGCCs as novel regulators of autophagy in the heart muscle and provides new insights into the effects of VGCC blockers on CMs homeostasis, that may underlie both noxious and cardioprotective effects.ca_ES
dc.description.sponsorshipThis work was supported by Instituto de Salud Carlos III (grantnumbers PI070357 to C.C. and RD12/0043/0018 to R.P.), and byGeneralitat de Catalunya (grant number 20145GR168 to R.P). C.P.was recipient of a predoctoral fellowship from Generalitat deCatalunya-AGAUR. A.D., R.P. and M.N. were recipients of predoc-toral fellowships from Universitat de Lleida.ca_ES
dc.language.isoengca_ES
dc.publisherElsevierca_ES
dc.relationMIECI/PN2004-2007/PI070357ca_ES
dc.relation.isformatofReproducció del document publicat a https://doi.org/10.1016/j.biocel.2015.09.010ca_ES
dc.relation.ispartofThe International Journal of Biochemistry & Cell Biology, 2015, vol. 68, p. 166–175ca_ES
dc.rights(c) Elsevier Ltd, 2015ca_ES
dc.subjectPharmacologyca_ES
dc.subjectCalcium channel blockersca_ES
dc.subjectCardiomyocytesca_ES
dc.subjectUnfolded protein responseca_ES
dc.subjectAutophagyca_ES
dc.titleVoltage-gated calcium channel blockers deregulate macroautophagy in cardiomyocytesca_ES
dc.typearticleca_ES
dc.identifier.idgrec023223
dc.type.versionpublishedVersionca_ES
dc.rights.accessRightsinfo:eu-repo/semantics/restrictedAccessca_ES
dc.identifier.doihttps://doi.org/10.1016/j.biocel.2015.09.010
dc.date.embargoEndDate10000-01-01


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