Associate editor: C.G. SobeyCardioprotective potential of annexin-A1 mimetics in myocardial infarction
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).
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The formyl peptide receptors FPR1 and FPR2 as targets for inflammatory disorders: recent advances in the development of small-molecule agonists
2024, European Journal of Medicinal ChemistryThe Annexin-A1 mimetic RTP-026 promotes acute cardioprotection through modulation of immune cell activation
2023, Pharmacological ResearchDevelopment of synthetic lipoxin-A4 mimetics (sLXms): New avenues in the treatment of cardio-metabolic diseases
2023, Seminars in ImmunologyCitation Excerpt :One of the first FPR2 agonists to be studied has been the Annexin-A1 (Anx-A1) anti-inflammatory protein, its peptidic mimetics Ac2–26, and the small molecule compound 17b and compound 43. Anx-A1 demonstrated cardio [180] and renal [181] protection in many disease models including AKI and myocardial infarction. Among Anx-A1 mimetic molecules, those that are still in pre-clinical stages, demonstrated great therapeutic potential in displaying cardio-protective effects in several experimental models: in particular, compound 17b, which protects from myocardial ischemia-reperfusion injuries [182], and compound 43 which preserves cardiac structure and function from post-myocardial infarction damage [183].
Therapeutic potential for targeting Annexin A1 in fibrotic diseases
2022, Genes and DiseasesCitation Excerpt :Annexin A1 accelerates neutrophils apoptosis by inducing calcium flux and reducing the expression of the anti-apoptosis factor B-cell lymphoma 2.26,33 At the inflammation site, monocytes differentiate into macrophages to remove abnormal cells and debris (i.e., efferocytosis), which prevents necrosis and release of inflammatory factors,27 including IL-1β, IL-6, TNF-α, and ROS. Annexin A1 induces monocytes differentiation into M2a+M2c− like cells, an anti-inflammatory and pro-resolving macrophage phenotype, produces and secretes IL-10.34,35
Biased agonism at adenosine receptors
2021, Cellular SignallingCitation Excerpt :One method correlating in vitro effects with in vivo outcomes considers the spectrum of pathways activated by a ligand as a signalling “fingerprint” that can be used to predict on-target therapeutic efficacy and/or adverse effect liability. This method has been successfully applied to both prospectively and retrospectively cluster compounds according to their unique signalling profile at the A1R, and other GPCRs [84,86,116]. However, despite the power in correlating signalling fingerprints with in vivo effects, clinical development would benefit from a mechanistic understanding of how in vitro signalling profiles are coupled to therapeutic and adverse outcomes.
Current state and future perspective of cardiovascular medicines derived from natural products
2020, Pharmacology and TherapeuticsCitation Excerpt :Deficiency of annexin -A1 leads to an increased level of cardiac necrosis, inflammation and fibrosis in MI (Qin et al., 2017). This observation is supported by the gain of function studies which demonstrated the administration of peptidomimetics agonists for formyl peptide receptor (FPR), Ac2-26 (endogenous ligand) and CGEN-855A (exogenous ligand) reduced neutrophil activation, migration and infiltration, attenuated cardiac and systemic inflammation, as well as reducing cardiac fibrosis and apoptosis induced by IR (Qin et al., 2015; Qin et al., 2019). Furthermore, a small-molecule agonist at the same receptor, Cmpd17b, activated components of the beneficial cell survival reperfusion injury salvage kinase (RISK) pathway such as extracellular regulated protein kinases 1/2 (Erk1/2) and protein kinases B (AKT) signaling pathways, with reduced activation of the detrimental pathway (calcium overload) in vitro.
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Both authors contributed equally to this work.