Multiple functions of angiotensin-converting enzyme 2 and its relevance in cardiovascular diseases

Angiotensin-converting enzyme 2 (ACE2) is a negative regulator of the renin-angiotensin system, and functions as the key SARS coronavirus receptor and stabilizer of neutral amino acid transporters. ACE2 catalyzes the conversion of angiotensin II to angiotensin 1-7, thereby counterbalancing ACE activity. Accumulating evidence indicates that the enzymatic activity of ACE2 has a protective role in cardiovascular diseases. Loss of ACE2 can be detrimental, as it leads to functional deterioration of the heart and progression of cardiac, renal, and vascular pathologies. Recombinant soluble human ACE2 protein has been demonstrated to exhibit beneficial effects in various animal models, including cardiovascular diseases. ACE2 is a multifunctional enzyme and thus potentially acts on other vasoactive peptides, such as Apelin, a vital regulator of blood pressure and myocardium contractility. In addition, ACE2 is structurally a chimeric protein that has emerged from the duplication of 2 genes: homology with ACE at the carboxypeptidase domain and homology with Collectrin in the transmembrane C-terminal domain. ACE2 has been implicated in the pathology of Hartnup's disease, a disorder of amino acid homeostasis, and, via its function in amino acid transport, it has been recently revealed that ACE2 controls intestinal inflammation and diarrhea, thus regulating the gut microbiome. This review summarizes and discusses the structure and multiple functions of ACE2 and the relevance of this key enzyme in disease pathogenesis.