MRP4 (ABCC4) as a potential pharmacologic target for cardiovascular disease. (May 2016)

• Record Type: Journal Article
• Authors: Belleville-Rolland, Tiphaine; Sassi, Yassine; Decouture, Benoit; Dreano, Elise; Hulot, Jean-Sébastien; Gaussem, Pascale; Bachelot-Loza, Christilla
• Is Part Of: Pharmacological research. Volume 107(2016:May)
• Page Start: 381
• Page End: 389
• Publication Date: 2016-05
• Subjects: ABC ATP-binding cassette -- AC adenylate cyclase -- AKAP A-kinase anchoring protein -- AR adenosine receptor -- CABG coronary artery bypass graft -- cAMP cyclic adenosine monophosphate -- cGMP cyclic guanosine monophosphate -- COX cyclooxygenase -- δ-SPD δ-storage pool deficiency -- MRP multidrug resistance protein -- MSD membrane-spanning domain -- NBD nucleotide-binding domain -- NO nitric oxide -- PDE phosphodiesterase -- PGI2 prostaglandin I2 -- PKA protein kinase A -- PKG protein kinase G -- sGC soluble guanylate cyclase -- SMC smooth muscle cell -- TXA2 thromboxane A2 -- VASP vasodilator-stimulated phosphoprotein; MRP4 -- ABCC4 -- cAMP -- Platelet -- Thrombosis -- Cardiovascular disease; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2016.04.002
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: This review focuses on multidrug resistance protein 4 (MRP4 or ABCC4) that has recently been shown to play a role in cAMP homeostasis, a key-pathway in vascular biology and in platelet functions. In vascular system, recent data provide evidence that inhibition of MRP4 prevents human coronary artery smooth muscle cell proliferation in vitro and in vivo, as well as human pulmonary artery smooth muscle cell proliferation in vitro and pulmonary hypertension in mice in vivo . In the heart, MRP4 silencing in adult rat ventricular myocytes results in an increase in intracellular cAMP levels leading to enhanced cardiomyocyte contractility. However, a prolonged inhibition of MRP4 can promote cardiac hypertrophy. In addition, secreted cAMP, through its metabolite adenosine, prevents adrenergically induced cardiac hypertrophy and fibrosis. Finally, MRP4 inhibition in platelets induces a moderate thrombopathy. The localization of MRP4 underlines the emerging concept of cAMP compartmentalization in platelets, which is a major regulatory mechanism in other cells. cAMP storage in platelet dense granules might limit the cAMP cytosolic concentration upon adenylate cyclase activation, a necessary step to induce platelet activation. In this review, we discuss the therapeutic potential of direct pharmacological inhibition of MRP4 in atherothrombotic disease, via its vasodilating and antiplatelet effects.