title: Arsenite modulates cardiac substrate preference by translocation of GLUT4, but not CD36, independent of mitogen-activated protein kinase signaling.
abstract: The protein thiol-modifying agent arsenite, a potent activator of stress signaling, was used to examine the involvement of MAPKs in the regulation of cardiac substrate uptake. Arsenite strongly induced p38 MAPK phosphorylation in isolated rat cardiac myocytes but also moderately enhanced phosphorylation of p42/44 ERK and p70 S6K. At the level of cardiomyocytic substrate use, arsenite enhanced glucose uptake dose dependently up to 5.1-fold but failed to stimulate long-chain fatty acid uptake. At the substrate transporter level, arsenite stimulated the translocation of GLUT4 to the sarcolemma but failed to recruit CD36 or FABPpm. Because arsenite did not influence the intrinsic activity of glucose transporters, GLUT4 translocation is entirely responsible for the selective increase in glucose uptake by arsenite. Moreover, the nonadditivity of arsenite-induced glucose uptake and insulin-induced glucose uptake indicates that arsenite recruits GLUT4 from insulin-responsive intracellular stores. Inhibitor studies with SB203580/SB202190, PD98059, and rapamycin indicate that activation of p38 MAPK, p42/44 ERK, and p70 S6K, respectively, are not involved in arsenite-induced glucose uptake. In addition, all these kinases do not play a role in regulation of cardiac glucose and long-chain fatty acid uptake by insulin. Hence, arsenite's selective stimulation of glucose uptake appears unrelated to its signaling actions, suggesting that arsenite acts via thiol modification of a putative intracellular protein target of arsenite within insulin-responsive GLUT4-containing stores. Because of arsenite's selective stimulation of cardiac glucose uptake, identification of this putative target of arsenite within the GLUT4-storage compartment may indicate whether it is a target for future strategies in prevention of diabetic cardiomyopathy.
authors.affiliation: Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, P.O. Box 616, NL-6200 MD Maastricht, The Netherlands. j.luiken@gen.unimaas.nl
authors.forename: Joost J F P
authors.initials: JJ
authors.lastname: Luiken
authors.forename: Iman
authors.initials: I
authors.lastname: Momken
authors.forename: Daphna D J
authors.initials: DD
authors.lastname: Habets
authors.forename: Mohammed
authors.initials: M
authors.lastname: El Hasnaoui
authors.forename: Will A
authors.initials: WA
authors.lastname: Coumans
authors.forename: Debby P Y
authors.initials: DP
authors.lastname: Koonen
authors.forename: Jan F C
authors.initials: JF
authors.lastname: Glatz
authors.forename: Arend
authors.initials: A
authors.lastname: Bonen
mesh_terms: D000818:Animals; D018053:Arsenites / Q000494:pharmacology*; D018955:CD36 Antigens / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D019893:Ribosomal Protein S6 Kinases / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D018053:Arsenites; D018955:CD36 Antigens; D005227:Fatty Acids; D051275:Glucose Transporter Type 4; C495694:Slc2a4 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose; C015001:arsenite