title: MRP4 (ABCC4) as a potential pharmacologic target for cardiovascular disease.
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.
authors.affiliation: Inserm UMR-S1140, Faculté de Pharmacie, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; AP-HP, Hôpital Européen Georges Pompidou, Service d⿿hématologie biologique, Paris, France.
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Belleville-Rolland
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Yassine
authors.initials: Y
authors.lastname: Sassi
authors.affiliation: Inserm UMR-S1140, Faculté de Pharmacie, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Decouture
authors.affiliation: Inserm UMR-S1140, Faculté de Pharmacie, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Dreano
authors.affiliation: AP-HP, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, F-75013 Paris, France; Sorbonne Universités, UPMC Univ. Paris 06, France.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hulot
authors.affiliation: Inserm UMR-S1140, Faculté de Pharmacie, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; AP-HP, Hôpital Européen Georges Pompidou, Service d⿿hématologie biologique, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Gaussem
authors.affiliation: Inserm UMR-S1140, Faculté de Pharmacie, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: christilla.bachelot-loza@parisdescartes.fr.
authors.forename: Christilla
authors.initials: C
authors.lastname: Bachelot-Loza
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000378:metabolism*; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*
chemical_list: D027425:ATP-Binding Cassette, Sub-Family C Proteins; C073492:ABCC4 protein, human
keywords: ABCC4; Cardiovascular disease; MRP4; Platelet; Thrombosis; cAMP