Ghrelin May Inhibit Inflammatory Response and Apoptosis During Ischemia-Reperfusion Injury

Abstract

Background: Ghrelin, a novel growth hormone-releasing peptide, has both anti-inflammatory and anti-apoptotic effects on human endothelial cells. We evaluated the protective effects of ghrelin against ischemia-reperfusion injury (IRI) in a murine heterotopic cervical heart transplantation model.

Methods: Donor hearts from C57BL/6J wild-type mice, which were kept in cold saline for 60 minutes, were heterotopically transplanted into C57BL/6J wild-type recipients. A day prior to heterotopic cervical heart transplantation, donor animals received either ghrelin (300 nmol/kg) or saline (0.3 mL) intraperitoneally. Upon reperfusion and postoperative day 1, ghrelin or saline was administered to the recipients. Donor hearts were procured on day 2.

Results: Ghrelin injection did not result in any adverse effects in donors or recipients. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells were significantly decreased in the ghrelin group (0.38% ± 0.21% vs 5.74% ± 3.68%; P < .001). Both cleaved caspase-3 activity and Bcl-2/Bax ratio from the ghrelin group were significantly reduced compared to those in the control. Furthermore, the phosphorylated Akt/Akt ratio was higher in the ghrelin group (0.44 ± 0.21 vs 0.14 ± 0.03; P = .043). Nuclear factor-kappa B p65 nuclear translocation was reduced in the ghrelin hearts compared to the controls (3.17% ± 1.84% vs 19.28% ± 13.14%; P = .009). Vascular cell adhesion molecule-1, intracellular adhesion molecule-1, nuclear factor-kappa B, and tumor necrosis factor alpha levels were also significantly reduced in the ghrelin-treated group. No significant difference was observed in 8-isoprostane production between groups.

Conclusion: Ghrelin inhibits the inflammatory response and apoptosis during transplant-related IRI. This study demonstrates the protective effects of ghrelin against IRI.