New Cardiovascular and Pulmonary Therapeutic Strategies Based on the Angiotensin-Converting Enzyme 2/Angiotensin-(1–7)/Mas Receptor Axis

Ferreira, Anderson J.; Murça, Tatiane M.; Fraga-Silva, Rodrigo A.; Castro, Carlos Henrique; Raizada, Mohan K.; Santos, Robson A. S.

Many advances have been achieved regarding the therapeutic regulation of the RAS. Current therapies based on the modulation of the RAS include the ACEi, ARBs, and renin inhibitors. In general, these drugs prevent or reverse endothelial dysfunction and atherosclerosis, reduce cardiovascular mortality and morbidity of patients with coronary artery disease, and hold antihypertensive effects [128] . Classically, the mechanisms of action of the ACEi and ARBs involve the blockade of the synthesis and actions of Ang II, respectively. However, the RAS is a complex hormonal system and, consequently, other mechanisms are likely implicated in the actions of these drugs [42, 86, 129] . They cause substantial increase in plasma levels of Ang-(1-7), leading to the assumption that their clinical effects might be partly mediated by this heptapeptide [42, 130] . Indeed, a variety of effects of the ACEi and ARBs can be abolished or attenuated by Mas antagonism, confirming the role of Ang-(1-7) in the actions of these compounds [129, 131] . The beneficial effects of Ang-(1-7) as well as its likely involvement in the effects of the ACEi and ARBs represent a strong evidence for the therapeutic potential of the activation of the ACE2/Ang-(1-7)/Mas axis (Figure 3 ). Ang-(1-7) Formulations. The beneficial effects of Ang-(1-7) are well known; however, the therapeutic utilization of this peptide is limited due to its unfavorable pharmacokinetic properties. Ang-(1-7) has a short half-life (approximately 10 seconds) since it is rapidly cleaved by peptidases [132] . Furthermore, Ang-(1-7) is degraded during its passage through the gastrointestinal tract when orally administrated. Thus, new strategies are crucial to make feasible the clinical application of Ang-(1-7) .