Hindawi Publishing Corporation Cardiology Research and Practice Volume 2012, Article ID 823193, 11 pages doi:10.1155/2012/823193 Review Article Targeting the ACE2 and Apelin Pathways Are Novel Therapies for Heart Failure: Opportunities and Challenges Seyyed M. R. Kazemi-Bajestani,1, 2 Vaibhav B. Patel,1, 3 Wang Wang,1, 2 and Gavin Y. Oudit1, 2, 3 1 Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada T6G 2S2 2 Department of Physiology, University of Alberta, Edmonton, AB, Canada T6G 2H7 3 Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, AB, Canada T6G 2G3 Correspondence should be addressed to Gavin Y. Oudit, gavin.oudit@ualberta.ca Received 12 December 2011; Accepted 21 February 2012 Academic Editor: Gregory Giamouzis Copyright © 2012 Seyyed M. R. Kazemi-Bajestani et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Angiotensin-converting enzyme 2 (ACE2)/Ang II/Ang 1–7 and the apelin/APJ are two important peptide systems which exert diverse eﬀects on the cardiovascular system. ACE2 is a key negative regulator of the renin-angiotensin system (RAS) where it metab- olizes angiotensin (Ang) II into Ang 1–7, an endogenous antagonist of Ang II. Both the prolonged activation of RAS and the loss of ACE2 can be detrimental as they lead to functional deterioration of the heart and progression of cardiac, renal, and vascular dis- eases. Recombinant human ACE2 in an animal model of ACE2 knockout mice lowers Ang II. These interactions neutralize the pres- sor and subpressor pathologic eﬀects of Ang II by producing Ang 1–7 levels in vivo, that might be cardiovascular protective. ACE2 hydrolyzes apelin to Ang II and, therefore, is responsible for the degradation of both peptides. Apelin has emerged as a promising peptide biomarker of heart failure. The serum level of apelin in cardiovascular diseases tends to be decreased. Apelin is recognized as an imperative controller of systemic blood pressure and myocardium contractility. Dysregulation of the apelin/APJ system may be involved in the predisposition to cardiovascular diseases, and enhancing apelin action may have important therapeutic eﬀects. 1. Introduction Angiotensin-converting enzyme 2 (ACE2)/Ang II/Ang 1–7 and apelin/APJ are two important peptide systems with diverse and fundamental cardiovascular protective eﬀects that may prevent or reverse a variety of vascular and cardiac disorders [1–3]. ACE2 is a monocarboxypeptidase which eﬀectively plays a key role as the central negative regulator of the renin-angiotensin system (RAS). ACE2 is of particular interest because it is an essential component of RAS which is possibly implicated in metabolizing angiotensin (Ang) II into Ang 1–7 [4]. These interactions counteract the pathologic eﬀects of Ang II by producing Ang 1–7, that is known to be cardiovascular protective. Ang II impairs cardiovascular function and enhances pressor and subpressor pathologic consequences, and hence Ang 1–7 protects against these pathological processes [1, 2]. Apelin is an endogenous peptide that is widely expressed in various organs as a 77 amino acid preproapelin. Several active fragments of apelin have been known (apelin-36, apelin-19, apelin-17, apelin-16, apelin-13, and apelin-12) which relatively share similar biological activities. In addition to the possibility of application of apelin as a heart failure (HF) biomarker, apelin also has direct biological eﬀects including vasodilatory and inotropic eﬀects [5]. Several previous studies have shown the cardioprotective eﬀect of ACE2 and apelin in all three steps of primary, secondary and tertiary prevention of HF (Figures 1 and 2). In this paper we summarize the current literature regarding the cardiovascu- lar eﬀects of ACE2 and apelin and their possible therapeutic applications. 2. Role of ACE2 and Apelin in Systemic and Pulmonary Hypertension Several previous studies demonstrated that ACE2 can mod- ulate blood pressure. Daily infusion of recombinant human