The Impact of ACE and ACE2 Gene Polymorphisms in Pulmonary Diseases Including COVID-19

The renin-angiotensin system (RAS) shows a strong expression in the lung where it functions both independently and in cooperation with its circulating equivalent. The hormonal cascade of RAS starts with the hydrolytic cleavage of the circulating, liver-derived angiotensinogen (AGT) by the protease renin (REN), that results in the formation of the decapeptide angiotensin I (ANG I). ANG I is then cleaved by the matrix metallopeptidase angiotensin-converting enzyme (ACE). The latter results in the formation of the peptide hormone with eight amino acids, angiotensin II (ANG II) the main RAS effector. ANG II by binding to its main receptor AT1R (Angiotensin II Type 1 Receptor) activates several signal transduction pathways and promotes vasoconstriction, as well as hypoxic, oxidative, inflammatory and proliferative events. The above constitute the ACE/ANGII/AT1R axis starting with ACE. The levels and consequently the actions of ANGII are counterbalanced by the activation of the ACE2/ANG1-7/MasR axis that is, respectively, controlled by the angiotensin-converting enzyme 2 (ACE2), an ACE homologue with the exact opposite role. ACE2 cleaves ANGII by hydrolyzing one peptide bond in its C-terminus. The result of this particular reaction is the formation of the heptapeptide hormone angiotensin 1-7 (ANG 1-7), that counterbalances the adverse effects of ANG II. ANG 1-7 gets alternatively proteolysed, also by ACE2, that hydrolyzes its secondary substrate, ANG I, resulting in the production of angiotensin 1-9 molecule that is afterwards cleaved by the ACE into ANG 1-7. ANG 1-7 exerts vasodilative, antioxidant, anti-inflammatory and anti-proliferative effects by binding to the Mas G protein-coupled receptor (MasR).