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

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• 作者：Tiphaine Belleville-Rolland^a ; ^b ; ^c ; ¹ ; Yassine Sassi^d ; ¹ ; Benoit Decouture^a ; ^b ; ¹ ; Elise Dreano^a ; ^b ; Jean-Sé ; bastien Hulot^e ; ^f ; Pascale Gaussem^a ; ^b ; ^c ; Christilla Bachelot-Loza^a ; ^b ; ^{christilla.bachelot-loza@parisdescartes.fr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：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 gu
• 刊名：Pharmacological Research
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：107
• 期：Complete
• 页码：381-389
• 全文大小：1859 K

文摘

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.