Dataset Information

Multidrug resistance-associated protein 4 regulates cAMP-dependent signaling pathways and controls human and rat SMC proliferation.

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.

SUBMITTER: Sassi Y

PROVIDER: S-EPMC2467383 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Multidrug resistance-associated protein 4 regulates cAMP-dependent signaling pathways and controls human and rat SMC proliferation.

Sassi Yassine Y Lipskaia Larissa L Vandecasteele Grégoire G Nikolaev Viacheslav O VO Hatem Stéphane N SN Cohen Aubart Fleur F Russel Frans G FG Mougenot Nathalie N Vrignaud Cédric C Lechat Philippe P Lompré Anne-Marie AM Hulot Jean-Sébastien JS

The Journal of clinical investigation 20080801 8

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 art ...[more]

PMID: 18636120

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Project description:Antiviral resistance is now the single most important factor in treatment failure using nucleos(t)ide analogues (NA). Primary drug resistance mutations refer to amino acid change(s) that result in reduced susceptibility to an antiviral agent. Secondary compensatory mutations restore replication defects associated with primary drug resistance and may be associated with low level reduced susceptibility. Several evolutionary pathways of drug resistant HBV have been observed in patients treated with NAs. It is possible that the drug resistance mutations selected with one agent may affect the efficacy of other NAs. Several major HBV-evolutionary NA-resistance pathways (rtM204I/V, rtN236T and rtA181T/V) have now been characterised. The rtM204V/I pathway is responsible for resistance to the L: -nucleosides, such as lamivudine (LMV), telbivudine (LdT) and clevudine (CLD), and also entecavir (ETV), whilst the rtN236T pathway is responsible for adefovir (ADV) and tenofovir (TFV) resistance. Both pathways are associated with clusters of secondary mutations that can affect subsequent treatment with NAs (rtT184G, rtS202I) such as ETV. The third pathway, rtA181T/V, is associated with resistance to LMV and ADV and is a potential multi-drug resistance pathway and will probably have an impact on TFV sensitivity, either alone or with the rtN236T. In naïve patients treated with ETV, atleast three mutations arising at the same time are required: rtL180M + rtM204V plus either one of rtT184, rtS202 or rtM250 codon changes. Finally, in highly drug-experienced patients, clusters of mutations such as rtA181T/I233V/N236T/M250L, all on the one dominant HBV genome, are being detected which are associated with multi-drug resistance. Sequential treatment with nucleos(t)ide analogue reverse transcriptase inhibitors (NRTI) promotes multidrug resistance. It is likely, therefore, that development of multi-drug resistance could be reduced by combination therapy optimised to individual viral phenotypes.

Dataset Information

Multidrug resistance-associated protein 4 regulates cAMP-dependent signaling pathways and controls human and rat SMC proliferation.

Publications

Multidrug resistance-associated protein 4 regulates cAMP-dependent signaling pathways and controls human and rat SMC proliferation.

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