Invited critical reviewApelin in acute myocardial infarction and heart failure induced by ischemia
Highlights
► Only animal studies concern the role of apelin–APJ system in myocardial ischemia. ► Less is known about apelin function in acute phase of myocardial infarction in human. ► Apelin–APJ system could be involved in myocardial protection in acute ischemia. ► Data concerning apelin role in acute myocardial infarction and heart failure have been reviewed.
Introduction
Apelin belongs to the adipokines − a term used to denote cytokines, growth factors, and other proteins produced and secreted by adipocytes. These factors are also called adipocytokines [1]. This does not imply that expression and production of such factors is restricted to adipocytes as most of these factors are also produced by a variety of other cell types. The term often refers to leptin and adiponectin, which are secreted by the adipocytes of adipose tissue. A variety of other factors are also released by adipose tissue in vitro and in vivo and these have been also termed collectively as adipokines or adipocytokines (TNF-alpha, IL-6, leptin, omentin, visfatin, adipsin, resistin, apelin, retinol binding protein rbp4) [2].
Section snippets
Overview of apelin physiology and pathophysiology
In 1993 O'Dowd et al. identified an endogenous ligand for the angiotensin-like 1 receptor (APJ) [3]. This is a ligand for one of the earliest, so called “orphan” G-protein-coupled receptors (GPCRs). GPCRs represent the largest group of transmembrane proteins responsible for transduction of a diverse array of extracellular signals. Recent progress in genome research revealed a total of about 300 GPCRs [4]. Approximately 140 of these novel GPCRs do not bind any known endogenous ligand and are
Animal studies
The majority of experimental data regarding the role of apelin in cardiovascular system has been conducted in rodents. Sparse studies used other animals. Del Ry et al. have been used a wild boar (Sus scrofa) model to establish its genoma sequence for apelin for future applications of molecular biology studies [20]. While other researchers, on the canine model, have investigated the influence of apelin on changes in intracellular sodium current, which may contribute to the apelin inotropic
Animal studies
The role of apelin−APJ in the pathogenesis of heart failure has received a great attention. Szokodi et al. were the first group to report downregulation of apelin mRNA in cardiac myocytes under cyclic stretch in vitro and in ventricular myocardium from two rat models of hypertensive heart failure [11]. In animal models of heart failure the expression of apelin and APJ is increased or maintained in animals with left ventricular hypertrophy and compensated heart failure, but downregulated in
Apelin as a therapeutic target in heart failure?
Japp and co-workers were the first to demonstrate an influence of acute administration of apelin-36 infusion on human cardiovascular system in vivo [51]. Apelin was injected into peripheral artery as well as intracoronary bolus was given in order to measure coronary blood flow and LV contractility and pressures. Intravenous infusion of apelin was given for the systemic hemodynamic study. They were able to demonstrate peripheral and coronary vasodilatation, improvement of myocardial
Conclusions
In summary, available data from animal and human studies suggest that apelin–APJ system is:
- 1.
upregulated in response to hypoxia/ischemia
- 2.
maintained or augmented in chronic pressure overload and the early stages of heart failure
- 3.
essentially downregulated in severe heart failure.
The studies confirm the validity of apelin as a new adipokine of cardiovascular importance. Still available data do not give responses to all questions. Existing studies provide sparse data. Experimental and clinical
References (51)
- et al.
A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11
Gene
(1993) - et al.
Novel neurotransmitters as natural ligands of orphan G-protein-coupled receptors
Trends Neurosci
(2001) - et al.
Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor
Biochem Biophys Res Commun
(1998) - et al.
Molecular properties of apelin: tissue distribution and receptor binding
Biochim Biophys Acta
(2001) - et al.
Emerging roles of apelin in biology and medicine
Pharmacol Ther
(2005) - et al.
Apelin signalling: a promising pathway from cloning to pharmacology
Cell Signal
(2005) - et al.
Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo
J Biol Chem
(2004) - et al.
Circulating and cardiac levels of apelin, the novel ligand of the orphan receptor APJ, in patients with heart failure
Biochem Biophys Res Commun
(2003) - et al.
Sequencing and cardiac expression of apelin in Sus scrofa
Pharmacol Res
(2009) - et al.
Modulation of canine cardiac sodium current by Apelin
J Mol Cell Cardiol
(2010)
Adrenomedullin gene expression is developmentally regulated and induced by hypoxia in rat ventricular cardiac myocytes
J Biol Chem
Apelin protects myocardial injury induced by isoproterenol in rats
Regul Pept
Hypoxia-inducible factor 1-alpha reduces infarction and attenuates progression of cardiac dysfunction after myocardial infarction in the mouse
J Am Coll Cardiol
Apelin reduces myocardial reperfusion injury independently of PI3K/Akt and P70S6 kinase
Regul Pept
Apelin is a novel islet peptide
Regul Pept
Vascular effects of apelin in vivo in man
J Am Coll Cardiol
The value of apelin-36 and brain natriuretic peptide measurements in patients with first ST-elevation myocardial infarction
Clin Chim Acta
Serum levels of apelin and ghrelin in patients with acute coronary syndromes and established coronary artery disease − KOZANI STUDY
Transl Res
Central and peripheral cardiovascular actions of apelin in conscious rats
Regul Pept
Down-regulation of cardiac apelin system in hypertrophied and failing hearts: possible role of angiotensin II–angiotensin type 1 receptor system
J Mol Cell Cardiol
Apelin protects heart against ischemia/reperfusion injury in rat
Peptides
Apelin: a new plasma marker of cardiopulmonary disease
Regul Pept
Utility of plasma apelin and other indices of cardiac dysfunction in the clinical assessment of patients with dilated cardiomyopathy
Regul Pept
Adipocytokines − novel link between inflammation and vascular function?
J Physiol Pharmacol
Adipose tissue: the new endocrine organ? A review article
Dig Dis Sci
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Platelet apelin receptor expression is reduced in patients with acute myocardial infarction
2021, Vascular PharmacologyCitation Excerpt :This observation may point to an association of platelet apelin receptor loss with cardiac tissue damage which is typically indicated by elevated troponin I. Analyses of the data regarding an aged- or BMI-related decrease of apelin receptor expression on platelets of patients with acute myocardial infarction did not show any significant effects (Supplements I). Since its discovery, growing evidence reveals that the apelin/apelin receptor system is an important regulator of cardiovascular homeostasis playing a role in the pathophysiology of various cardiac diseases [27–30]. The apelin receptor is expressed in a wide range of tissues with preponderance for the cardiovascular system [15].
Apelin/APJ expression in the heart and kidneys of hypertensive rats
2018, Acta HistochemicaAssessment of Apelin Serum Levels in Persistent Atrial Fibrillation and Coronary Artery Disease
2016, American Journal of the Medical SciencesCitation Excerpt :Apelin is biologically active in myocardium, cardiac endothelium, vascular endothelium, veins and arteries, which suggest that cardiovascular system may be the main target of apelin.23,24 Moreover, apelin is one of the most potent endogenous factors with positive inotropic effect and might play an important role in cardiac electrophysiology,8,11,24 and thus AF pathogenesis. Previous studies showed that the serum levels of apelin decrease in both patients with AF and CAD compared to healthy subjects.20-22