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.