%0 Journal Article %1 Sassi2008 %A Sassi, Y. %A Lipskaia, L. %A Vandecasteele, G. %A Nikolaev, V. O. %A Hatem, S. N. %A Aubart, F. Cohen %A Russel, F. G. %A Mougenot, N. %A Vrignaud, C. %A Lechat, P. %A Lompre, A. M. %A Hulot, J. S. %D 2008 %J J Clin Invest %K & *Signal AMP AMP/metabolism Animals Cell Coronary Cultured Cyclic Element-Binding Expression Gene Humans Male Multidrug Muscle, Proliferation Protein/metabolism Proteins/antagonists Rats Regulation Resistance-Associated Response Smooth, Transduction Vascular/cytology/*metabolism Vessels/cytology Wistar inhibitors/*metabolism %N 8 %P 2747-57 %T Multidrug resistance-associated protein 4 regulates cAMP-dependent signaling pathways and controls human and rat SMC proliferation %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18636120 %V 118 %X The second messengers cAMP and cGMP can be degraded by specific members of the phosphodiesterase superfamily or by active efflux transporters, namely the multidrug resistance-associated proteins (MRPs) MRP4 and MRP5. To determine the role of MRP4 and MRP5 in cell signaling, we studied arterial SMCs, in which the effects of cyclic nucleotide levels on SMC proliferation have been well established. We found that MRP4, but not MRP5, was upregulated during proliferation of isolated human coronary artery SMCs and following injury of rat carotid arteries in vivo. MRP4 inhibition significantly increased intracellular cAMP and cGMP levels and was sufficient to block proliferation and to prevent neointimal growth in injured rat carotid arteries. The antiproliferative effect of MRP4 inhibition was related to PKA/CREB pathway activation. Here we provide what we believe to be the first evidence that MRP4 acts as an independent endogenous regulator of intracellular cyclic nucleotide levels and as a mediator of cAMP-dependent signal transduction to the nucleus. We also identify MRP4 inhibition as a potentially new way of preventing abnormal VSMC proliferation.

@article{Sassi2008, abstract = {The second messengers cAMP and cGMP can be degraded by specific members of the phosphodiesterase superfamily or by active efflux transporters, namely the multidrug resistance-associated proteins (MRPs) MRP4 and MRP5. To determine the role of MRP4 and MRP5 in cell signaling, we studied arterial SMCs, in which the effects of cyclic nucleotide levels on SMC proliferation have been well established. We found that MRP4, but not MRP5, was upregulated during proliferation of isolated human coronary artery SMCs and following injury of rat carotid arteries in vivo. MRP4 inhibition significantly increased intracellular cAMP and cGMP levels and was sufficient to block proliferation and to prevent neointimal growth in injured rat carotid arteries. The antiproliferative effect of MRP4 inhibition was related to PKA/CREB pathway activation. Here we provide what we believe to be the first evidence that MRP4 acts as an independent endogenous regulator of intracellular cyclic nucleotide levels and as a mediator of cAMP-dependent signal transduction to the nucleus. We also identify MRP4 inhibition as a potentially new way of preventing abnormal VSMC proliferation.}, added-at = {2010-12-14T18:12:02.000+0100}, author = {Sassi, Y. and Lipskaia, L. and Vandecasteele, G. and Nikolaev, V. O. and Hatem, S. N. and Aubart, F. Cohen and Russel, F. G. and Mougenot, N. and Vrignaud, C. and Lechat, P. and Lompre, A. M. and Hulot, J. S.}, biburl = {https://www.bibsonomy.org/bibtex/2e3b6af2e9f4a26795c1d306906572d97/pharmawuerz}, endnotereftype = {Journal Article}, interhash = {119299378115699857a646a6d7808231}, intrahash = {e3b6af2e9f4a26795c1d306906572d97}, issn = {0021-9738 (Print) 0021-9738 (Linking)}, journal = {J Clin Invest}, keywords = {& *Signal AMP AMP/metabolism Animals Cell Coronary Cultured Cyclic Element-Binding Expression Gene Humans Male Multidrug Muscle, Proliferation Protein/metabolism Proteins/antagonists Rats Regulation Resistance-Associated Response Smooth, Transduction Vascular/cytology/*metabolism Vessels/cytology Wistar inhibitors/*metabolism}, month = Aug, note = {Sassi, Yassine Lipskaia, Larissa Vandecasteele, Gregoire Nikolaev, Viacheslav O Hatem, Stephane N Cohen Aubart, Fleur Russel, Frans G Mougenot, Nathalie Vrignaud, Cedric Lechat, Philippe Lompre, Anne-Marie Hulot, Jean-Sebastien Research Support, Non-U.S. Gov't United States The Journal of clinical investigation J Clin Invest. 2008 Aug;118(8):2747-57.}, number = 8, pages = {2747-57}, shorttitle = {Multidrug resistance-associated protein 4 regulates cAMP-dependent signaling pathways and controls human and rat SMC proliferation}, timestamp = {2010-12-14T18:22:56.000+0100}, title = {Multidrug resistance-associated protein 4 regulates cAMP-dependent signaling pathways and controls human and rat SMC proliferation}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18636120}, volume = 118, year = 2008 }