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.