Angiotensin-Converting Enzyme 2

T here is a "new kid on the block" in the control of the renin-angiotensin system (RAS).The discovery of angiotensin (Ang)-converting enzyme (ACE)2, a catabolic enzyme, that cleaves the octapeptide, Ang II into a septapeptide, Ang-(1-7), 1,2 has opened up new vistas in the way we think about the regulation and biological effects of Ang II.ACE 2 was originally discovered in yeast 3 as a gene product that codes for a protein that is a homolog of the more widely known protease ACE.ACE2 cleaves the C-terminal amino acid from Ang II and other peptides.For many years, the work of Ferrario and Chappel 4 provided evidence that Ang-(1-7) operated in the central nervous system, as well as in the peripheral circulation to produce effects that were, in general, opposite to that of Ang II.Recently, the discovery that Ang-(1-7) binds to a specific membrane receptor, the mas receptor, [5][6][7] suggests that this metabolite may play a regulatory role in cell signaling and organ function.Clearly, the balance between the classic ACE and ACE2 will determine the physiological effect of activation of the RAS.Furthermore, the potential for therapeutic targeting of ACE2 and its role in the pathogenesis of various diseases such as hypertension and heart failure is intriguing.To further understand the potential for ACE 2 in the brain to alter sympathetic function and drinking, 2 well-known effects of central Ang II, Feng et al, in this issue of Circulation Research, 8 used adenoviral transfection techniques to overexpress ACE2 in the mouse brain.Overexpression was prominent in the subfornical organ (SFO), an area involved in sympathetic regulation and thirst in response to Ang II. 9 This structure is heavily endowed with Ang type 1 receptors (AT 1 R).Because the SFO is devoid of a blood-brain barrier relative to the majority of the brain, it is well suited to "sense" both cerebrospinal fluid and circulating substances.Therefore, the SFO is an ideal structure to test the hypothesis that overexpression of ACE2 alters responses to Ang II.There are 2 striking results presented in this study.The first relates to the physiological responses to ACE2 overexpression when challenged by intracerebroventricular Ang II.Both the pressor and drinking responses were dramatically reduced in The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.