Ectodomain Shedding of ACE and ACE2 as Regulators of Their Protein Functions

The renin-angiotensin system (RAS) plays a major role in regulating the cardiovascular, renal, respiratory and central nervous systems. Angiotensin-converting enzyme (ACE) and a newly identified homologue of ACE, angiotensinconverting enzyme 2 (ACE2), are regulators of the RAS. These enzymes, however, have distinct substrate specificity and physiological roles. There is evidence that a balance between ACE and ACE2 expression and activities plays an important role in maintaining normal organ physiology and also in the pathogenesis of various diseases. Thus understanding regulation of the two enzymes could have therapeutic implications. Both ACE and ACE2 are type I transmembrane glycoproteins in which the catalytic domains are located in their ectodomains. These ectoenzymes undergo proteolytic cleavage from the cell surface and this cellular process is known as ectodomain shedding. Ectodomain shedding results in release of the enzymatically active segments into the interstitial space and circulation. Both ACE and ACE2 also function as cell surface receptors that initiate intracellular signaling that can influence gene expression. Thus ectodomain shedding could influence various functions of ACE and ACE2. Recent evidence indicates that ectodomain shedding of these proteins is a highly regulated and versatile process. This review focuses on ectodomain shedding of ACE and ACE2 and summarizes what is known about the molecular and cellular mechanisms, the related clinical findings and potential therapeutic implications. Keywords: ACE, ACE2, ectodomain shedding, ectoenzyme, receptor, soluble form, the renin-angiotensin system, monoclonal antibodies, Therapeutic implications, CaM inhibitor