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

• Published in: The Journal of clinical investigation Vol. 118; no. 8; pp. 2747 - 2757
• Main Authors: Sassi, Yassine, Lipskaia, Larissa, Vandecasteele, Grégoire, Nikolaev, Viacheslav O, Hatem, Stéphane N, Cohen Aubart, Fleur, Russel, Frans G, Mougenot, Nathalie, Vrignaud, Cédric, Lechat, Philippe, Lompré, Anne-Marie, Hulot, Jean-Sébastien
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.08.2008
• Subjects: Animals; Biomedical research; Carotid arteries; Cell Proliferation; Cells, Cultured; Coronary vessels; Coronary Vessels - cytology; Cyclic AMP - metabolism; Cyclic AMP Response Element-Binding Protein - metabolism; Cyclic guanylic acid; Gene Expression Regulation; Genetic aspects; Humans; Ion channels; Male; Multidrug Resistance-Associated Proteins - antagonists & inhibitors; Multidrug Resistance-Associated Proteins - metabolism; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Physiological aspects; Proteins; Rats; Rats, Wistar; Signal Transduction; Veins & arteries; France
• DOI: 10.1172/JCI35067
• ISSN: 0021-9738

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.