Effects of structural analogues of apelin-12 in acute myocardial infarction in rats

Abstract

Objective:To examine cardioprotective effects of Ρ-terminal fragment of adipokine apelin-12 (A12), its novel structural analogue [MeArg1, NLe10]-A12 (I), and [d-Ala12]-A12 (II), a putative antagonist of APJ receptor, employing in vivo model of ischemia/reperfusion (I/R) injury.Materials and Methods:Peptides were synthesized by the automatic solid phase method using Fmoc technology. Anesthetized open-chest male Wistar rats were subjected to left anterior descending (LAD) coronary artery occlusion and coronary reperfusion. Hemodynamic variables and electrocardiogram (ECG) were monitored throughout the experiment. Myocardial injury was assessed by infarct size (IS), activity of necrosis markers in plasma, and metabolic state of the area at risk (AAR).Results:Intravenous injection of A12, I, or II at the onset of reperfusion led to a transient reduction of the mean arterial pressure. A12 or I administration decreased the percent ratio of IS/AAR by 40% and 30%, respectively, compared with control animals which received saline. Both peptides improved preservation of high-energy phosphates, reduced lactate accumulation in the AAR, and lowered CK-MB and LDH activities in plasma at the end of reperfusion compared with these indices in control. Treatment with II did not significantly affect either the IS/AAR, % ratio, or activities of both markers of necrosis compared with control. The overall metabolic protection of the AAR in the treated groups increased in the following rank: II < A12 < I.Conclusions:The structural analogue of apelin-12 [MeArg1, NLe10]-A12 may be a promising basis to create a new drug for the treatment of acute coronary syndrome.

Regulation of the endothelial apelin/APJ system by hemodynamic fluid flow

“…How apelin-12 is actually produced remains to be determined. In general, peptidases may be responsible for proteolytic cleavage of preproapelin [39]. The only known enzyme responsible for the degradation of preproapelin is angiotensin II converting enzyme 2 (ACE2) giving rise to the isoform apelin-13 [40].…”

Antioxidant Action of Apelin-12 Peptide and Its Structural Analog In Vitro

“…These fi ndings suggest that previously found moderation of oxidative stress (decrease in the content of ROS and FRO products as well as up-regulation of antioxidant enzymatic activity) paralleled with a decrease in myocardial reperfusion damage in ex vivo and in vivo models induced by C-terminal fragment of natural peptide apelin and its structural analogs [2,6,9,10,12] cannot be comprehensively explained by direct antioxidant action of these peptides. Probably, inhibition of production of the short-lived ROS and MDA (the product of lipid FRO) resulting from up-regulation of SOD, catalase, and glutathione peroxidase in ischemic-reperfused heart is one of the major protective mechanisms induced by apelins [2,12].…”

“…Previously we demonstrated that C-terminal fragment of natural peptide apelin composed of 12 amino acids H-ArgPro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe-OH (apelin-12, A12) and its synthetic structural analog H-(N α Me)Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-NlePro-Phe-OH (AI) mitigated damage to the heart during experimental ischemia and reperfusion. The protective effects of A12 and AI are related to moderation of cardiomyocytic membrane damage and promotion of cardiac energy metabolism recovery during reperfusion [3,9]. The mechanisms underlying the effects of apelin are little studied.…”

The protective effect of apelin on ischemia/reperfusion injury

“…Apelin-12 and its structural analog were involved in the upregulation of cardiac antioxidant defense systems and attenuation of lipid peroxidation in ex vivo and in vivo models of myocardial I/R injury [21,24]. As we know, I/R injury could induce myocardial infarction [31].…”