Elsevier

Pharmacology & Therapeutics

Volume 148, April 2015, Pages 47-65
Pharmacology & Therapeutics

Associate editor: C.G. Sobey
Cardioprotective potential of annexin-A1 mimetics in myocardial infarction

https://doi.org/10.1016/j.pharmthera.2014.11.012Get rights and content

Abstract

Myocardial infarction (MI) and its resultant heart failure remains a major cause of death in the world. The current treatments for patients with MI are revascularization with thrombolytic agents or interventional procedures. These treatments have focused on restoring blood flow to the ischemic tissue to prevent tissue necrosis and preserve organ function. The restoration of blood flow after a period of ischemia, however, may elicit further myocardial damage, called reperfusion injury. Pharmacological interventions, such as antioxidant and Ca2+ channel blockers, have shown premises in experimental settings; however, clinical studies have shown limited success. Thus, there is a need for the development of novel therapies to treat reperfusion injury. The therapeutic potential of glucocorticoid-regulated anti-inflammatory mediator annexin-A1 (ANX-A1) has recently been recognized in a range of systemic inflammatory disorders. ANX-A1 binds to and activates the family of formyl peptide receptors (G protein-coupled receptor family) to inhibit neutrophil activation, migration and infiltration. Until recently, studies on the cardioprotective actions of ANX-A1 and its peptide mimetics (Ac2-26, CGEN-855A) have largely focused on its anti-inflammatory effects as a mechanism of preserving myocardial viability following I–R injury. Our laboratory provided the first evidence of the direct protective action of ANX-A1 on myocardium, independent of inflammatory cells in vitro. We now review the potential for ANX-A1 based therapeutics to be seen as a “triple shield” therapy against myocardial I–R injury, limiting neutrophil infiltration and preserving both cardiomyocyte viability and contractile function. This novel therapy may thus represent a valuable clinical approach to improve outcome after MI.

Section snippets

Overview of myocardial ischemia–reperfusion injury

Cardiovascular disease (CVD), particularly myocardial infarction (MI) and stroke, is the leading cause of death and disability worldwide. The World Health Organization (WHO) has estimated that 17.3 million people died from CVD in 2008, which represented 30% of all global deaths (World Health Organization, Le Good et al., 1998). The major underlying cause of CVD is atherosclerosis, which together with thromboembolism, can result in the blockage of blood vessels, leading to ischemia. MI can be

Overview of ANX-A1 and its N-terminal peptides

ANX-A1, previously known as lipocortin-1, is a 37 kDa protein comprising 348 amino acids. First discovered as a second messenger of GC actions, ANX-A1 was initially shown to mediate the inhibitory effect of GCs on the activity of phospholipase A2 (PLA2) (Flower and Blackwell, 1979, Blackwell et al., 1980). ANX-A1 is a member of the annexin protein superfamily, which is comprised of at least 12 distinct Ca2+ and phospholipid-binding proteins. Their structure consists of a core region of 4 (as is

Overview of FPR receptors

In a striking example of convergence in function, the FPR2 receptor was discovered independently as both the receptor for the inflammation-resolving, trihydroxy-polyunsaturated fatty acid, LXA4 and named aspirin-triggered lipoxin receptor (ALXR), as well as its identification as the receptor for the GC effector, ANX-A1, initially named formyl peptide receptor-like receptor 1 (FPRL-1). For a period of time, these separate nomenclatures were maintained while the field established the single

ANX-A1 protection in I–R

The protective actions of ANX-A1 and its peptides have been reported in I–R injury in several vascular beds, including heart, kidney, gut and brain (D'Amico et al., 2000, La, D'Amico, et al., 2001, La, Tailor, D'Amico, Flower and Perretti, 2001, Gavins et al., 2005, Gavins et al., 2006, Gavins et al., 2007, Peskar et al., 2009, Facio et al., 2011). This evidence has been obtained using both exogenous administration of ANX-A1 and its peptide mimetics, as well as mice deficient in endogenous

Concluding remarks

Following myocardial I–R injury, loss of both cardiac contractility and muscle viability are evident. Rescue of cardiac contractile function in addition to preservation of cell viability, could offer an effective therapeutic strategy for myocardial infarction. ANX-A1-based therapies might potentially be seen as a “triple shield” therapy in myocardial I–R injury, limiting neutrophil infiltration and preserving both cardiomyocyte viability and LV contractile function. We propose that ANX-A1 thus

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgments

This work was supported in part by National Health and Medical Research Council (NHMRC) of Australia project grants, including ID1045140 (to RHR, XMG and YHY) and ID1067547 (to AGS), and supported in part by the Victorian Government's Operational Infrastructure Support Program. RHR is an NHMRC Senior Research Fellow (ID472673 and ID1059960).

References (284)

  • S.M. Albelda et al.

    Adhesion molecules and inflammatory injury

    FASEB J

    (1994)
  • A.L. Alessandri et al.

    Resolution of inflammation: mechanisms and opportunity for drug development

    Pharmacol Therapeut

    (2013)
  • M.P. Ambrose et al.

    Corticosteroids increase lipocortin I in alveolar epithelial cells

    Am J Respir Cell Mol Biol

    (1990)
  • J.L. Anderson et al.

    2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 Guidelines for the management of patients with unstable angina/Non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines

    Circulation

    (2011)
  • F. Arslan et al.

    Innate immune signaling in cardiac ischemia

    Nat Rev Cardiol

    (2011)
  • S. Arur et al.

    Annexin I is an endogenous ligand that mediates apoptotic cell engulfment

    Dev Cell

    (2003)
  • A.S. Baas et al.

    Differential activation of mitogen-activated protein kinases by H2O2 and O2- in vascular smooth muscle cells

    Circ Res

    (1995)
  • B.A. Babbin et al.

    Annexin A1 regulates intestinal mucosal injury, inflammation, and repair

    J Immunol

    (2008)
  • E.B. Babiychuk et al.

    Fluorescent annexin A1 reveals dynamics of ceramide platforms in living cells

    Traffic

    (2008)
  • Y.S. Bae et al.

    Differential activation of formyl peptide receptor signaling by peptide ligands

    Mol Pharmacol

    (2003)
  • Y.S. Bae et al.

    Identification of peptides that antagonize formyl peptide receptor-like 1-mediated signaling

    J Immunol

    (2004)
  • C. Bandeira-Melo et al.

    A novel effect for annexin 1-derived peptide ac2-26: reduction of allergic inflammation in the rat

    J Pharmacol Exp Ther

    (2005)
  • E. Beaulieu et al.

    Role of GILZ in immune regulation, glucocorticoid actions and rheumatoid arthritis

    Nat Rev Rheumatol

    (2011)
  • I.M.E. Beck et al.

    Crosstalk in inflammation: the interplay of glucocorticoid receptor-based mechanisms and kinases and phosphatases

    Endocr Rev

    (2009)
  • S. Bena et al.

    Annexin A1 interaction with the FPR2/ALX receptor: identification of distinct domains and downstream associated signaling

    J Biol Chem

    (2012)
  • M. Benoit et al.

    Macrophage polarization in bacterial infections

    J Immunol

    (2008)
  • M.E. Bianchi

    DAMPs, PAMPs and alarmins: all we need to know about danger

    J Leukoc Biol

    (2007)
  • G.J. Blackwell et al.

    Macrocortin: a polypeptide causing the anti-phospholipase effect of glucocorticoids

    Nature

    (1980)
  • K.E. Blume et al.

    Cleavage of annexin A1 by ADAM10 during secondary necrosis generates a monocytic “find-me” signal

    J Immunol

    (2012)
  • K.E. Blume et al.

    Cell surface externalization of Annexin A1 as a failsafe mechanism preventing inflammatory responses during secondary necrosis

    J Immunol

    (2009)
  • V. Brancaleone et al.

    Evidence for an anti-inflammatory loop centered on polymorphonuclear leukocyte formyl peptide receptor 2/lipoxin A4 receptor and operative in the inflamed microvasculature

    J Immunol

    (2011)
  • P.J. Buchanan et al.

    Lipoxin A(4)-mediated KATP potassium channel activation results in cystic fibrosis airway epithelial repair

    Am J Physiol Lung Cell Mol Physiol

    (2013)
  • R.W. Burli et al.

    Potent hFPRL1 (ALXR) agonists as potential anti-inflammatory agents

    Bioorg Med Chem Lett

    (2006)
  • E. Camors et al.

    Annexins and Ca2+ handling in the heart

    Cardiovasc Res

    (2005)
  • D.L. Carden et al.

    Pathophysiology of ischaemia–reperfusion injury

    J Pathol

    (2000)
  • D. Caron et al.

    Annexin A1 is regulated by domains cross-talk through post-translational phosphorylation and SUMOYlation

    Cell Signal

    (2013)
  • L.P. Chapman et al.

    Evidence for a role of the adenosine 5′-triphosphate-binding cassette transporter A1 in the externalization of annexin I from pituitary folliculo-stellate cells

    Endocrinology

    (2003)
  • P. Chatelain et al.

    Neutrophil accumulation in experimental myocardial infarcts: relation with extent of injury and effect of reperfusion

    Circulation

    (1987)
  • K. Chen et al.

    A critical role for the g protein-coupled receptor mFPR2 in airway inflammation and immune responses

    J Immunol

    (2010)
  • K. Chen et al.

    Formylpeptide receptor-2 contributes to colonic epithelial homeostasis, inflammation, and tumorigenesis

    J Clin Invest

    (2013)
  • N. Chiang et al.

    The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo

    Pharmacol Rev

    (2006)
  • P. Christia et al.

    Targeting inflammatory pathways in myocardial infarction

    Eur J Clin Invest

    (2013)
  • P. Christmas et al.

    Selective secretion of annexin 1, a protein without a signal sequence, by the human prostate gland

    J Biol Chem

    (1991)
  • T. Christophe et al.

    The synthetic peptide Trp-Lys-Tyr-Met-Val-Met-NH2 specifically activates neutrophils through FPRL1/lipoxin A4 receptors and is an agonist for the orphan monocyte-expressed chemoattractant receptor FPRL2

    J Biol Chem

    (2001)
  • A. Cilibrizzi et al.

    6-Methyl-2,4-Disubstituted Pyridazin-3(2H)-ones: A Novel Class of Small-Molecule Agonists for Formyl Peptide Receptors

    J Med Chem

    (2009)
  • G. Cirino et al.

    Anti-inflammatory actions of an N-terminal peptide from human lipocortin 1

    Br J Pharmacol

    (1993)
  • A. Civelek et al.

    Leukocyte-depleted secondary blood cardioplegia attenuates reperfusion injury after myocardial ischemia

    J Thorac Cardiovasc Surg

    (2003)
  • A.R. Clark

    Anti-inflammatory functions of glucocorticoid-induced genes

    Mol Cell Endocrinol

    (2007)
  • A.R. Clark et al.

    Maps and legends: the quest for dissociated ligands of the glucocorticoid receptor

    Pharmacol Ther

    (2012)
  • E. Cristante et al.

    Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications

    Proc Natl Acad Sci U S A

    (2013)
  • F. D'Acquisto et al.

    Impaired T cell activation and increased Th2 lineage commitment in Annexin-1-deficient T cells

    Eur J Immunol

    (2007)
  • F. D'Acquisto et al.

    Pro-inflammatory and pathogenic properties of Annexin-A1: the whole is greater than the sum of its parts

    Biochem Pharmacol

    (2013)
  • C.W. D'Acunto et al.

    The complex understanding of Annexin A1 phosphorylation

    Cell Signal

    (2014)
  • J. Dalli et al.

    Proresolving and tissue-protective actions of annexin A1-based cleavage-resistant peptides are mediated by formyl peptide receptor 2/lipoxin A4 receptor

    J Immunol

    (2013)
  • J. Dalli et al.

    Annexin A1 N-terminal derived Peptide ac2-26 exerts chemokinetic effects on human neutrophils

    Front Pharmacol

    (2012)
  • J. Dalli et al.

    Annexin 1 mediates the rapid anti-inflammatory effects of neutrophil-derived microparticles

    Blood

    (2008)
  • A.S. Damazo et al.

    Endogenous annexin A1 counter-regulates bleomycin-induced lung fibrosis

    BMC Immunol

    (2011)
  • A.S. Damazo et al.

    Critical protective role for annexin 1 gene expression in the endotoxemic murine microcirculation

    Am J Pathol

    (2005)
  • A.S. Damazo et al.

    Spatial and temporal profiles for anti-inflammatory gene expression in leukocytes during a resolving model of peritonitis

    J Immunol

    (2006)
  • M. D'Amico et al.

    Lipocortin 1 reduces myocardial ischemia–reperfusion injury by affecting local leukocyte recruitment

    FASEB J

    (2000)
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    Both authors contributed equally to this work.

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