Human catestatin peptides differentially regulate infarct size in the ischemic–reperfused rat heart

Abstract

In acute myocardial infarction increased plasma levels of chromogranin A is correlated with decreased survival. At the human chromogranin A gene locus there are two naturally occurring amino acid substitution variants within the catestatin region, i.e. Gly 364 Ser and Pro 370 Leu, displaying differential potencies towards inhibition of nicotinic cholinergic agonist-evoked catecholamine secretion from sympathochromaffin cells and different degrees of processing from the prohormone. Here, we examine whether two of the variants and the wild type catestatin may affect the development of infarct size during ischemic reperfusion in the Langendorff rat heart model. The hearts were subjected to regional ischemia followed by reperfusion in the presence or absence of synthetic variants of human catestatin. Compared to the Gly 364 Ser variant both the wild type and the Pro 370 Leu variant increased infarct size while decreasing the cardiac levels of phosphorylated Akt and two of its downstream targets, FoxO1 and BAD. In conclusion, these findings suggest that, in contrast to the Gly 364 Ser variant, the wild type catestatin and the Pro 370 Leu variant (allele frequency ~0.3%) increased myocardial infarct size via a mechanism involving dephosphorylation of Akt and the two downstream targets during ischemic reperfusion in the isolated rat heart.

Catestatin reduces myocardial ischaemia/reperfusion injury: involvement of PI3K/Akt, PKCs, mitochondrial KATP channels and ROS signalling

“…Risk area and infarct-size assessed in hearts perfused with only inhibitors (groups [8][9][10][11][12] were similar to those observed in I/R control group (Fig.2B). This lack of effects on I/R injury has been already reported [14,35,39,[41][42][43][44].…”

Chromogranin A: a paradoxical player in angiogenesis and vascular biology

“…In the latter study two forms of catestatincontaining CgA fragments were detected, a 55 kDa form being most prominent in the control heart. Intriguingly, the experimental I/R procedure significantly increased the percentage of a catestatin-containing 27 kDa peptide in the necrotic zones at the expense of the 55 kDa form, indicating that the experimental conditions as such had caused CgA processing [47], distinctly different from the previously reported processing into the vasostatin-1 like, betagranin-containing peptides [48]. CgA is also present in the murine heart.…”

“…The outcome depends, however, on the mode of ischemia. After global ischemia post-conditioning with catestatin decreased the final reperfusion injury [46], while catestatin significantly enhanced the infarct size when the ex vivo rat heart had been exposed to regional ischemia [47]. In the latter study two forms of catestatincontaining CgA fragments were detected, a 55 kDa form being most prominent in the control heart.…”

Functional Genetic Variants of the Catecholamine-Release-Inhibitory Peptide Catestatin in an Indian Population

“…Intriguingly, the CST-Ser-364 peptide also displayed diminished potency (as compared with CST-WT) to regulate infarct size in the regionally ischemic-reperfused rat heart, likely to be mediated through a receptor(s) other than nAChR (44). Therefore, it appears that structural differences (viz.…”