Vascular angiotensin-converting enzyme 2: lord of the ring?

Through the actions of its main biological peptide, angiotensin (Ang) II, the renin–angiotensin system (RAS) has been implicated in atherosclerosis.1,2 The proatherogenic effect of Ang II may involve a variety of proinflammatory mechanisms that are largely independent from its effect on blood pressure.1 Ang II promotes monocyte and endothelial cell activation, as well as leukocyte recruitment and adhesion to the atherosclerotic plaque.3 This peptide also increases vascular oxidative stress, an effect that may also contribute to atherogenesis.4 The formation of Ang II by angiotensin-converting enzyme (ACE)-dependent and ACE-independent pathways has been viewed as the main determinant of systemic and local Ang II levels. With the discovery of ACE2, an enzyme that degrades Ang II, there has been increased interest in the regulation of Ang II levels through the degradation pathway.5,6 ACE2 is a homolog of ACE that cleaves the octapeptide Ang II into Ang-(1-7) by removing a single amino acid phenylalanine from its C-terminal end.7,8 Because of its ability to degrade Ang II, ACE2 is viewed as a counter-regulator of Ang II overactivity.8,9 This property could have therapeutic implications. We suggested that ACE2 could be renoprotective, especially when associated with low levels of ACE.10 Increasing evidence suggests that ACE2 plays a protective role in cardiovascular disease and other pathologies.5,11 In this issue of Circulation Research, Thomas et al12 report their findings of a cross between atherosclerosis-prone apolipoprotein (Apo)E knockout (KO) and ACE2 KO mice to study the effects of ACE2 deficiency on the development of atherosclerosis. Genetic ACE2 ablation led to enhanced vascular inflammation and plaque formation in ApoE KO mice. In ApoE-replete mice, ACE2 deficiency was also associated with increased expression of inflammatory markers, such as interleukin-6, monocyte chemoattractant protein-1, and vascular cell adhesion molecule-1, suggesting that these differences were indeed related to the deficiency of ACE2 in the vasculature. This important study provides strong evidence for a proinflammatory and proatherogenic effect associated with deficiency of ACE2 both in vivo and in vitro. What could the mechanism be? In the context of the known proinflammatory and proatherogenic actions of Ang II, impaired degradation of this peptide owing to ACE2 deficiency could explain their findings. In other words, Ang II accumulation systemically and/or locally within the vasculature could be responsible for the observed increases in vascular inflammation, as seen in the ACE2 KO, and enhanced plaque formation, as seen in the ApoE/ACE2 double KO.12 The issue, however, is complicated by the fact that genetic ACE2 ablation may or may not lead to demonstrable Ang II overactivity, as judged by increased levels of circulating or tissue Ang II levels. Marked differences have been reported between 3 different ACE2-deficient mouse lines in terms of cardiovascular phenotype and basal Ang levels.12–15 The line originally described by Crackower et al,8 which was used in this study,12 has increased levels of Ang II in kidneys, hearts, and plasma. By contrast, the other available mouse lines13,14 do not have any overt differences in the levels of these peptides. These differences in phenotypes between ACE2deficient lines cannot be easily explained by differences in the gene disruption methodology or differences in genetic backgrounds.15 ACE2 deficiency in the other 2 ACE2deficient lines, however, is not without consequence; rather, the metabolism of Ang II is clearly impaired, as demonstrated by increased plasma and kidney levels of Ang II when this peptide is infused. Moreover, this is associated with marked worsening of Ang II–induced hypertension.13,16 That treatment with the ACE inhibitor, perindopril, reduced plaque accumulation in ApoE/ACE2 double KO mice is evidence for the involvement of Ang II in the atherogenic response observed in this model.12 The degree of conferred protection was less than that observed following ACE inhibitor administration to ApoE KO mice. ACE2 activity in the vasculature was decreased following the administration of perindopril,12 which is surprising considering that others have shown increases in ACE2 activity following the administration of either ACE inhibitors or Ang II type 1 receptor blockers.17,18 Nevertheless, the improvement in atherogenesis with the ACE inhibitor implies Ang II dependency and is consistent with the expected impairment in the degradation of this peptide in the face of ACE2 deficiency. It is possible, however, that peptides other than Ang II could also be altered in mice with genetic ACE2 ablation and may contribute to the amplification of vascular inflammation and atherogenesis. For instance, ACE2 removes the C-terminal residue from apelin and des-Arg9-bradykinin, as well as other vasoactive peptides, such as neurotensin and kinetensin.19 The status of these peptides in the ACE2 KO is currently unknown. Atherosclerotic lesions express matrix metalloproteinases (MMP), which possess proteolytic activity. For instance, The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Nephrology and Hypertension, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Ill. Correspondence to Daniel Batlle, Division of Nephrology/Hypertension, Tarry 4-735, 303 E Chicago Ave, Chicago, IL 60611. E-mail [email protected] (Circ Res. 2010;107:822-824.) © 2010 American Heart Association, Inc.