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Therapeutic Implications of the Vasoprotective Axis of the Renin-Angiotensin System in Cardiovascular Diseases

Year: 2009

Type: article

Abstract: D espite the tremendous success obtained using the current pharmacotherapy, especially angiotensin (Ang)converting enzyme (ACE) inhibitors (ACEis) and Ang II receptor blockers (ARBs), the prevalence of cardiovascular diseases (CVDs) remains high around the world.The overall death rate in the United States alone in 2005 was 278.9 per 100 000 people. 1 These unprecedented numbers have stimulated researchers to consider the development of new strategies and targets to control these diseases.Since its discovery, the renin-Ang system (RAS) has been considered an important target to manage the disturbances of the cardiovascular system.In fact, RAS blockers represent the main class of drugs in the treatment of hypertension and CVDs. 2 Recent genomic and proteomic studies have led to significant advances in our understanding of the RAS and in experimental methods for studying regulatory mechanisms influenced by the RAS.Thus, demonstrating the existence of a counterregulatory axis within the RAS, constituted by ACE2, Ang-(1-7), and the Mas receptor, has established a new concept for this system, that is, the classic narrow cascade formed by ACE, Ang II, and Ang II type 1 receptor (AT 1 ) has been replaced by a flexible hormonal system with many bioactive peptides, receptors, enzymes, and interactions among these components.[2][3][4] Consequently, follow-up studies have revealed new possibilities and targets to better control CVD.In this review, we discuss the following: (1) the current status of the RAS with an emphasis on evidence for the existence of the ACE2/Ang-(1-7)/Mas axis; (2) the role of this axis in the pathophysiology of the cardiovascular, renal, pulmonary, and central nervous systems; (3) the potential of this protective axis for the development of novel CVD therapeutics; and (4) future perspectives. Autoregulation of the RAS: ACE2/Ang-(1-7)/Mas Receptor AxisThe RAS consists of 2 distinct and counterregulatory axes (Figure).The classic ACE/AngII/AT 1 R axis is responsible for the vasoconstrictive, proliferative, hypertensive, and fibrotic actions of the RAS.Its hyperactivity is associated with hyper-tension and CVDs, such as cardiac hypertrophy, heart failure, stroke, coronary artery disease, and end-stage renal disease.This axis is the primary target for the actions of the RAS blockers.The ACE2/Ang-(1-7)/Mas axis constitutes an alternative axis that represents an intrinsic mechanism to induce vasoprotective actions by counterregulating the ACE/AngII/AT 1 R axis, thus inducing many beneficial effects in CVDs.Ang II type 2 receptors may also contribute to this counterregulation.5 The counterregulatory concept of the RAS is emerging, and studies have established a key role for its main component, ACE2.ACE2 is a monocarboxypeptidase of which the active site domain shares Ϸ42% homology with the active site of ACE. 6 It is found in the plasma membranes of virtually all organs as an ectoenzyme and in the plasma and urine in a soluble active form.4 Ang I and Ang II are the principal substrates for this enzyme.The impact of ACE2 on the metabolism of other cardiovascular relevant peptides has not been completely elucidated.6 ACE2 is one of the principal Ang-(1-7)-forming enzymes.4,6 Because of the higher affinity of ACE2 for Ang II, Ang-(1-7) generation from Ang II is physiologically more relevant than from Ang I. 6 As a result, ACE2 plays a crucial role in maintaining the balance between both axes of the RAS, and a chronic and sustained imbalance may lead to pathophysiology of the cardiovascular, renal, pulmonary, and central nervous systems.Currently, the physiological signals that tip the balance between the 2 axes of the RAS to favor a pathological state remain unknown.It is suggested that the equilibrium between the expression/activity of the 2 ACEs is crucial.7 Furthermore, ACE2 may represent an endogenous autoregulatory mechanism within the RAS, because it decreases Ang II levels in favor of Ang-(1-7) formation.The concept that ACE2 is capable of balancing the activities of both axes of the RAS is a central argument in designating this enzyme as a target for the development of novel antihypertensive and cardioprotective drugs. Biological Actions of the ACE2/Ang-(1-7)/Mas Axis Cardiovascular SystemIncreasing evidence indicates that the ACE2/Ang-(1-7)/Mas axis plays a critical role in cardiovascular homeostasis and

Source: Hypertension

DOI: 10.1161/hypertensionaha.109.140145