3. ACE2 is the modulator of RAAS
Angiotensin-converting enzyme 2 (ACE2), the main active peptide of
renin-angiotensin-aldosterone system (RAAS), is a homologue to the
carboxypeptidase angiotensin-converting enzyme (ACE), which generates
angiotensin Ⅱ (Ang Ⅱ). As the name of RAAS indicates, renin and
angiotensin are two critical components forming the system. Renin is the
first and rate-limiting step in the RAAS cascade, without the renin
enzyme there are no angiotensin. Angiotensinogen is the precursor to all
angiotensin and is converted via renin to form angiotensin Ⅰ (Ang Ⅰ).
Under the physiological conditions, the protease renin cleaves
angiotensinogen to generate Ang Ⅰ, then ACE cleaves Ang Ⅰ to Ang Ⅱ,
which contact with Ang Ⅱ receptor type 1 receptor (AT1R) and Ang Ⅱ
receptor type 2 receptor (AT2R). The proinflammatory effects of Ang Ⅱ
are mediated through AT1R(Fleming et al. , 2006). Studies have
shown that the ACE/ Ang Ⅱ/ AT1R axis can induce vasoconstriction,
hypertension, inflammation, proliferation and fibrosis, and ACE is the
key enzyme in the regulation of Ang Ⅱ production. However, in 2000, the
homologue of ACE, ACE2 has been discovered that it negatively regulates
the activated renin-angiotensin system by degrading Ang Ⅱ to the
heptapeptide angiotensin (1-7) (Ang (1-7)), which reacts with MAS
receptor (MasR)(Rice et al. , 2004). There are various methods to
regulate the balance between ACE/ Ang Ⅱ/ AT1R axis and ACE2/Ang
(1-7)/Mas, including recombinant human ACE2 (rhACE2), ACE inhibitors
(ACEI) and angiotensin receptor blockers (ARBs). As reported, ACE2 has a
strong affinity with Ang Ⅱ type 1 and type 2 receptors, thus it has been
identified as an important counter regulatory mechanism to the classic
RAAS. ACE2 controls the pressor/depressor balance of the RAAS by ⅰ)
converting angiotensin Ⅰ to angiotensin (1-9), limiting the number of
substrate available to generate angiotensin Ⅱ, ⅱ) converting angiotensin
Ⅱ to angiotensin (1-7), restricting angiotensin Ⅱ stimulation of the AT1
receptor and ⅲ) generation of angiotensin (1-7), which is capable of
binding to its own receptor, Mas receptor to oppose the pressor actions
of the AT1 receptor. The ACE2/Ang (1-7)/Mas receptor axis has been shown
to play protective roles in numerous disease models including heart
failure, hypertension, injury, fibrosis and metabolic syndrome(Mirabitoet al. , 2019). Upregulating ACE2 may transfer the balance of RAAS
to the ACE2/Ang (1-7)/Mas axis for protection. Most available evidence
supports a counter-regulatory role for Ang (1-7) by opposing many
actions of Ang Ⅱ on AT1R receptors, especially vasoconstriction,
inflammation and proliferation. In addition, ACE2 also has been
confirmed as an essential receptor for SARS coronavirus infections as
well as a protective molecule against lethal lung failure in SARS(Liet al. , 2003). In fact, SARS receptor function of ACE2 is
independent of its catalytic activities for Ang Ⅱ degradation, whereas
ACE2-mediated Ang Ⅱ degradation is important for lung protection from
SARS pathogenesis.