TY - JOUR
T1 - MRP4 (ABCC4) as a potential pharmacologic target for cardiovascular disease
AU - Belleville-Rolland, Tiphaine
AU - Sassi, Yassine
AU - Decouture, Benoit
AU - Dreano, Elise
AU - Hulot, Jean Sébastien
AU - Gaussem, Pascale
AU - Bachelot-Loza, Christilla
N1 - Publisher Copyright:
© 2016 Elsevier Ltd. All rights reserved.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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.
AB - 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.
KW - ABCC4
KW - Cardiovascular diseasea
KW - MRP4
KW - Platelet
KW - Thrombosis
KW - cAMP
UR - http://www.scopus.com/inward/record.url?scp=84962910030&partnerID=8YFLogxK
U2 - 10.1016/j.phrs.2016.04.002
DO - 10.1016/j.phrs.2016.04.002
M3 - Review article
C2 - 27063943
AN - SCOPUS:84962910030
SN - 1043-6618
VL - 107
SP - 381
EP - 389
JO - Pharmacological Research
JF - Pharmacological Research
ER -