8.1 Angiotensin-(1-7) [Ang-(1-7)] and its first finds
Angiotensin-(1-7) (Ang-(1-7)) is an important component of the Renin-Angiotensin System (RAS), which regulates blood pressure and electrolyte balance (Santos et al, 2018). It is a heptapeptide with therapeutic potential demonstrated in the late 1980s by reducing blood pressure in an in vivo model (Campagnole-Santos et al., 1989). Ang-(1-7) is generated by the catalysis of Angiotensin I (Ang I) or mostly Angiotensin II (AngII) by the Angiotensin-Converting Enzyme (ACE) 2 anchored in the cytoplasmic membrane of the cell. Ang-(1-7) and AngII usually have opposing effects and act by binding specifically to its Mas receptor (MasR) which is a type of G protein-coupled receptor (GPCR). Activation of this receptor leads to a signaling cascade that triggers the production of nitric oxide. This ACE2/Ang-(1-7)/MasR axis is then called the RAS alternative pathway and is usually referred to as the protective counterpart of the RAS. Counter-regulation of AngII signaling by Ang-(1-7) reduces reactive oxygen species (ROS) generation, cell proliferation, fibrosis, and controls inflammation pathways by decreasing TGF-β/NF-kB signaling and proinflammatory molecules (Sampaio et al, 2007; Gallagher and Tallant, 2004; Ni et al, 2012). As a result, the administration of Ang-(1-7) or MasR agonists has emerged as a potential therapeutic strategy to counteract the negative effects of Ang II in various diseases. Finally, the discovery of Ang-(1-7) and its role as a protective peptide in the RAS alternative pathway has opened new avenues for research and therapeutic interventions. Further studies are needed to fully elucidate the molecular mechanisms and clinical implications of Ang-(1-7), but its therapeutic potential in modulating the RAS and mitigating the detrimental effects of Ang II holds great promise.
In addition to its well-established effects on the cardiovascular and renal systems, numerous studies have now demonstrated the anti-inflammatory and pro-resolving properties of (Ang-(1-7) in various models of chronic and acute non-infectious inflammation. These models include asthma, arthritis, and ischemia. Studies have shown that Ang-(1-7) exerts beneficial effects in these inflammatory conditions. For example, it has been found to reduce airway inflammation and improve lung function in asthma models (El-Hashim et al., 2012; da Silveira et al., 2010). In arthritis models, Ang-(1-7) has been shown to attenuate joint inflammation and cartilage destruction (Zeng et al., 2009). Additionally, in ischemia models, Ang-(1-7) has demonstrated protective effects by reducing tissue damage and promoting tissue repair (Jiang et al., 2012; Santos et al., 2014).
The underlying mechanisms by which Ang-(1-7) exerts its anti-inflammatory and pro-resolving effects are multifaceted. Figure 1 provides a comprehensive overview of the documented effects of therapeutic administration of Ang-(1-7) in various models of viral and bacterial infections. In mouse models and in vitro experiments, Ang-(1-7) has been found to induce apoptosis of neutrophils and eosinophils, promote the clearance of apoptotic cells (efferocytosis), facilitate the migration of macrophages, and induce the polarization of macrophages towards an M2 anti-inflammatory phenotype (de Carvalho Santuchi et al., 2019; Melo et al., 2021; Barroso et al., 2017; Magalhaes et al., 2018; Pan et al., 2021). Cellular and molecular actions contribute to the resolution of inflammation, tissue repair, and the restoration of homeostasis. Findings from these studies highlight the potential therapeutic implications of Ang-(1-7) in the management of various inflammatory conditions. However, further research is still needed to fully understand the precise mechanisms underlying its effects and to explore its therapeutic potential in clinical settings.