Review Article - · PDF fileAPA Angiotensinogen Ang III Ang II Ang 1–9 Ang 1–7 Ang 1–5 Ang I (1–10) Fibronectin, TGF β1, NF-κB, TNFα, Figure 1: The enzymatic cascade involved

Hindawi Publishing CorporationCardiology Research and PracticeVolume 2012, Article ID 823193, 11 pagesdoi:10.1155/2012/823193

Review Article

Targeting the ACE2 and Apelin Pathways Are Novel Therapies forHeart 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 2S22 Department of Physiology, University of Alberta, Edmonton, AB, Canada T6G 2H73 Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, AB, Canada T6G 2G3

Correspondence should be addressed to Gavin Y. Oudit, [email protected]

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 CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Angiotensin-converting enzyme 2 (ACE2)/Ang II/Ang 17 and the apelin/APJ are two important peptide systems which exertdiverse 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 17, an endogenous antagonist of Ang II. Both the prolonged activation of RAS and the lossof 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 17 levels in vivo, that might be cardiovascular protective. ACE2hydrolyzes apelin to Ang II and, therefore, is responsible for the degradation of both peptides. Apelin has emerged as a promisingpeptide biomarker of heart failure. The serum level of apelin in cardiovascular diseases tends to be decreased. Apelin is recognizedas an imperative controller of systemic blood pressure and myocardium contractility. Dysregulation of the apelin/APJ system maybe 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 17and apelin/APJ are two important peptide systems withdiverse and fundamental cardiovascular protective effectsthat may prevent or reverse a variety of vascular and cardiacdisorders [13]. ACE2 is a monocarboxypeptidase whicheffectively plays a key role as the central negative regulatorof the renin-angiotensin system (RAS). ACE2 is of particularinterest because it is an essential component of RAS which ispossibly implicated in metabolizing angiotensin (Ang) II intoAng 17 [4]. These interactions counteract the pathologiceffects of Ang II by producing Ang 17, that is known tobe cardiovascular protective. Ang II impairs cardiovascularfunction and enhances pressor and subpressor pathologicconsequences, and hence Ang 17 protects against thesepathological processes [1, 2].

Apelin is an endogenous peptide that is widely expressedin 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 additionto the possibility of application of apelin as a heart failure(HF) biomarker, apelin also has direct biological effectsincluding vasodilatory and inotropic effects [5]. Severalprevious studies have shown the cardioprotective effect ofACE2 and apelin in all three steps of primary, secondary andtertiary prevention of HF (Figures 1 and 2). In this paper wesummarize the current literature regarding the cardiovascu-lar effects of ACE2 and apelin and their possible therapeuticapplications.

2. Role of ACE2 and Apelin in Systemic andPulmonary Hypertension

Several previous studies demonstrated that ACE2 can mod-ulate blood pressure. Daily infusion of recombinant human

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2 Cardiology Research and Practice

Vasoconstriction

Vascular inflammation

Cell proliferation

Fibrosis

Hypertrophy

Effects: Activates: Increases:

Decreases:Increases:

Effects:

Vasodilation

Endothelial protection

Antiproliferative

Antifibrotic

Antioxidative stress

PKC, MAPK/ERK 1/2JNK, JAK-STAT3,PI3K-Akt

NO release,eNOS activation,SOD,Catalase activity

Profilin, procollagen

IL-6, MCP-1, VCAM-1,T cell activity,MMIF, MMP, ROS,NADPH oxidase

Lipid peroxidation,NADPH oxidase activity,

Cox-2, MAPK, ERK1/2 ,CHOP, GRP-78

Atherosclerosis

Hypertension

Remodeling/heart failure

Diabetic cardiovascular complications

Pulmonary arterial hypertension

Atrial/ventricular arrhythmia

A1TR Mas R

ACE2therapy

ACE2therapy

PCP

CPA

Chyma

se PEP

ACEACE2

ACE2

ACE NEP

Renin

APA

Angiotensinogen

Ang III Ang II

Ang 19

Ang 17 Ang 15

Ang I (110)

Fibronectin, TGF 1,

NF- B, TNF,

Figure 1: The enzymatic cascade involved in the renin-angiotensin system, key receptor systems, and the biological effects mediatedby Ang II and Ang 17. Solid black lines, enzymatic pathways; Broken lines, peptide agonist interacting with its key receptor; Greenarrow, stimulatory effects; Red arrow, pathologic effects; Green bars; inhibitory effects. ACE2: angiotensin-converting enzyme; Akt: proteinkinase B; Ang: angiotensin; APA: aminopeptidase A; AT1R Ang II type 1 receptor; CHOP: CCAAT/enhancer binding protein homologousprotein; Cox-2: cyclooxygenase-2; CPA: carboxypeptidase A; eNOS: endothelial synthase; ERK: extracellular signal-regulated kinase; GRP-78: glucose regulated protein; IL-6: interleukin-6; JAK-STAT: Janus Kinase- signal transducer and activator of transcription system; JNK:C-jun-N-terminal kinase; MAPK: mitogen activated protein kinase; Mas R: Ang 17 receptor; MCP-1: monocyte cheomattractant protein 1;MMIF: macrophage migration inhibitory factor; MMP: matrix metalloproteinase; NADPH: nicotinamide adenine dinucleotide phosphate;NEP: neutral endopeptidase; NF-kappaB: nuclear factor kappa-light-chain-enhancer of activated B cells; NO: nitric oxide; PCP: prolylcarboxypeptidase (also known as angiotensinase C); PEP: prolyl endopeptidase; PI3K: phosphatidylinositol 3-kinases; PKC: protein kinase C;ROS: reactive oxygen species; SOD: superoxide dismutase; TGF1, transforming growth factor1; TNF : tumor necrosis factor ; VCAM-1:vascular cell adhesion molecule-1.

ACE2 (rhACE2) (2 mg/kg1/d1) reduces the Ang II-inducedhypertension in mice, by reducing Ang II-mediated activa-tion of enhanced extracellular signal-regulated kinase 1/2(ERK1/2), protein kinase C (PKC) pathways and renalfibrosis [6]. It is suggested that ACE2 expression is decreasedin the spontaneously hypertensive rats before the markedonset of hypertension [7]. It is believed that impaired renallevel of ACE2 contributes to hypertension in humans [8].Exposure of cultured human umbilical artery smooth muscle

cells (HUASMCs) to Ang II results in a significant increasein the mRNA and protein expression of profilin-1, recentlylinked to cytoskeleton remodeling by activation of the hyper-trophic signaling through mitogen activated protein kinase(MAPK), ERK1/2 and C-jun-N-terminal kinase (JNK), inconjunction with reduced ACE2 activity [9]. Enhancedprofilin-1 expression and MAPK signaling in HUASMCs inresponse to Ang II was noticeably reduced by rhACE2 inan Ang 17-dependent manner [9]. Improvement of ACE2

Cardiology Research and Practice 3

Cardiomyocytes

Inotropic effect: activation of PLC, PKC,

Antagonize Ang II effects :PAI-1 inhibition,Rho kinase inhibition

AF amelioration: propagation of actionpotential and contractility

Vasculature

Modulates abnormal aortic vascular tone in

phosphorilation

Diminish AAA formation:

Endothelium

Endothelium-dependent vasorelaxation:NO release: cAMP accumulation inhibition (?)

Collateralization and neovascularization

HTNAtherosclerosis AngiogenesisPAH AAAPAH Atherosclerosis I/R injury ArrhythmiaVasodilation Remodeling

Apelin

ER-stress: CHOP,Caspase12,JNKinflammation:hs-CRP,IL6,TNF

pulmonary endothelial cell hemostasis:BMP,eNOS,AMPK

response to Ang II:Akt and eNOS

TNF, IL-6aortic MCSF expression, MCP1,

ROS:NADPH oxidase in vascularsmooth muscle cells

pulmonary artery muscle cell proliferation

Protect I/R injury: PI3K/Akt, AMPK andP44/42 phosphorilation; SOD activity,ERK 1/2 ROS, CHOP, Caspase 12,andJNK

and Na+ exchangers

Contractility

/Ca+2Na+/H+,

Figure 2: Diverse effects of apelin on cardiovascular system. Black arrows, effects of apelin on various targets; Green arrows and red bars,favorable stimulatory and inhibitory effects of apelin on cardiovascular system respectively; AAA: abdominal aorta aneurysm; AF: atrialfibrillation; Akt: protein kinase B; AMPK: adenosine monophosphate-activated protein kinase; BMP: bone morphogenetic protein; CHOP:CCAAT/enhancer binding protein homologous protein; eNOS: endothelial synthase; hs-CRP: high sensitivity C-reactive protein; ER-stress:endoplasmic reticulum stress; ERK: extracellular signal-regulated kinase; HTN: hypertension; I/R: ischemia reperfusion; IL-6: interleukin6; JNK: C-jun-N-terminal kinase; MCSF: macrophage colony stimulating factor; MCP-1: mon