Modified APJ Receptor Peptide Ligands as Postconditioning Drugs in Myocardial Ischaemia/Reperfusion Injury

The apelin/APJ system is involved in many physiological functions and pathophysiological effects in cardiovascular diseases, making it a promising drug target. This narrative review briefly summarizes data on experimental conditioning of the heart with modified structural analogues of apelin-12. Apelin-12 analogues resistant to proteolytic cleavage in human plasma were synthetized by targeted substitution of amino acid residues in the structure of natural apelin-12 by an automated solid-phase method using Fmoc technology. These peptides are able to mimic the protective effect of apelin-12 in both ex vivo and in vivo models of ischaemia/reperfusion (I/R) myocardial injury. Intravenous administration of apelin-12 analogues at the onset of reperfusion reduces the size of acute myocardial infarction in rats, preserves the metabolic and antioxidant state of the area at risk during reperfusion, and improves cardiomyocyte membrane integrity. Postconditioning effects are mediated by signaling via PLC and survival kinases, PI3K and MEK1/2, with further activation of downstream targets, NO synthase and mitochondrial K-ATP channels, and sarcolemmal Na+/H+ and Na+/Ca2+ exchangers. Given the role of apelin/APJ in cardiovascular diseases, future perspectives of development of pharmacological postconditioning with apelin-12 analogues are discussed. This strategy may provide important therapeutic benefits in the treatment of cardiovascular disease.