Review Article The Angiotensin-Converting Enzyme 2/Angiotensin-(1–7)/Mas receptor axis: A potential target for treating thrombotic diseases Rodrigo A. Fraga-Silva 1 ; Danielle G. Da Silva 1 ; Fabrizio Montecucco 2,3 ; François Mach 2 ; Nikolaos Stergiopulos 1 ; Rafaela F. da Silva 1,4 ; Robson A. S. Santos 4 1 Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; 2 Division of Cardiology, Geneva University Hospitals, Faculty of Medicine, Foundation for Medical Researches, Geneva, Switzerland; 3 First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy; 4 National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, Biological Science Institute, Federal University of Minas Gerais, Brazil Summary Despite many therapeutic advances leading to increasingly effective drug treatments, thrombotic events (such as ischaemic stroke, pulmon- ary embolism, deep venous thrombosis and acute myocardial infarc- tion) still represent a major worldwide cause of morbidity and mortal- ity. Remarkable effort has been made to identify new drug targets. There is growing evidence indicating that the recently described counter-regulator axis of the renin-angiotensin system (RAS), composed of Angiotensin-Converting Enzyme 2 (ACE2), Angioten- Correspondence to: Robson A. Souza dos Santos, MD, PhD Departamento de Fisiologia e Biofísica Federal University of Minas Gerais Av. Antonio Carlos, 6627 – UFMG, 31270–901 Belo Horizonte, MG, Brasil Tel.: +55 31 3409 2956 E-mail: santos@icb.ufmg.br sin-(1–7) and the Mas receptor, has protective effects against thrombo- sis. In addition, it could be considered as a promising target for treating or preventing this disease. In this narrative review, we focused on the recent findings of the role of the ACE2/Angiotensin-(1–7)/Mas axis on the haemostatic process and its therapeutic potential. Keywords Angiotensin-(1–7), Angiotensin Converting Enzyme 2, Receptor Mas, thrombosis, platelet Financial support: This research was funded by the Brazilian Swiss Joint Research Program (BSJRP) to F. Mach, N. Stergiopulos, and R.A.S Santos. This research was funded by EU FP7, Grant number 201668, AtheroRemo to F. Mach. This work was also supported by the Swiss National Science Foundation Grants to F. Mach (#310030–118245) and F. Montecucco (#32003B-134963/1). Received: June 13, 2012 Accepted after major revision: August 21, 2012 Prepublished online: October 23, 2012 doi:10.1160/TH12-06-0396 Thromb Haemost 2012; 108: 1089–1096 Introduction Thrombotic events (such as ischaemic stroke, pulmonary embol- ism, deep venous thrombosis, mesenteric ischaemia and acute cor- onary syndrome) are the major complications of some chronic cardiovascular diseases (CVD), such as hypertension, athero- sclerosis and diabetes mellitus (1, 2). Despite various therapeutic advances that have led to increasingly effective drug treatments, thrombogenic events still represent a major worldwide cause of morbidity and mortality (3, 4). Haemostatic disorders are common in several vascular diseases (3). In normal circumstances, the intact endothelium prevents pla- telet adhesion and activation through several mechanisms, includ- ing endothelial cell production of prostacyclin (PGI2) and nitric oxide (NO) (5). Endothelial disruption and deep intimal injury caused by plaque rupture lead to the exposure of components, such as collagen and von Willebrand factor (vWF) (6). Sub- sequently, platelets directly adhere to collagen or vWF via glyco- protein Ib-V-IX complex. Local platelet activation stimulates addi- tional platelet recruitment by releasing potent mediators, such as adenosine diphosphate, serotonin, and thromboxane A2. The acti- vation of the coagulation cascade occurs concomitantly, leading to fibrin strand formation, which strengthens the platelet plug (7). Under pathological conditions, the hyperactive haemostasis pro- cess may result in an exacerbation of the thrombus formation and consequently clinical thrombotic syndromes (3, 5). The renin-angiotensin system (RAS) is a major hormonal regu- lator of blood pressure and hydro-electrolyte balance (8), and it also participates in haemostasis (9). It has been reported that an in- creased activity of some RAS components is associated with a higher risk of acute thrombosis by destabilizing atherosclerotic plaques (10), promoting endothelial dysfunction and enhancing platelet activity and coagulation (10, 11). RAS supports a series of enzymatic reactions that culminate in the generation of Angiotensin (Ang) II by the angiotensin convert- ing enzyme (ACE). Ang II is the main effector of RAS, acting pri- marily through the AT1 receptor and promoting adverse cardio- vascular phenotypes (12). Currently, this classical concept of a lin- ear renin-angiotensin axis has been expanded, including novel players, such as ACE2 (13–15) (an ACE homologue enzyme) and the Mas receptor (16). ACE2 catalyses the conversion of Ang II to the heptapeptide Ang-(1–7) (13, 17, 18). Ang-(1–7) has been re- 1089 © Schattauer 2012 Thrombosis and Haemostasis 108.6/2012 For personal or educational use only. No other uses without permission. All rights reserved. Downloaded from www.thrombosis-online.com on 2013-01-08 | IP: 128.179.134.129