Ghrelin, a Novel Growth Hormone-Releasing Peptide, Inhibits Inflammatory Response and Apoptosis during Ischemic Reperfusion Injury Following Murine Heart Transplantation

Abstract

Purpose Ghrelin , a novel growth hormone-releasing peptide, has both anti-inflammatory and anti-apoptotic effects on human endothelial cells . Ischemic reperfusion injury (IRI) is a multi-factorial inflammatory condition and an important risk factor for cardiac allograft vasculopathy . We evaluated the protective effects of ghrelin against IRI following murine heterotopic cervical heart transplantation (HCHT). Methods Donor hearts of C57BL/6J mice, which were kept in cold saline for 60 minutes were heterotopically transplanted into C57BL/6J recipients (n = 7 each). A day prior to HCHT, donor animals received ghrelin 300 nmol/kg intraperitoneally or saline (0.3ml). Upon reperfusion and on postoperative day 1, ghrelin or saline was administered. Donor hearts were procured on postoperative day 2. Results Ghrelin injection did not result in any adverse effects on the donors. All animals (n = 7 each) in both groups successfully survived to postoperative day 2. As a measure of apoptosis , TUNEL-positive cells were significantly decreased in the ghrelin groups (0.38±0.21% vs. 5.74±3.68%; p = 0.0004). NF-kB p65 nuclear translocation was also reduced in the ghrelin groups compared to the control (3.17±1.84% vs. 19.28±13.14%; p = 0.0095). VCAM-1 (p = 0.0322), ICAM-1 (p = 0.0484) and NF-kB (p = 0.0130) levels were also significantly reduced in ghrelin-treated groups. No significant difference was observed in oxidative injury, as measured by 8-isoprostane production between groups (47.67±13.14 pg/mg vs. 95.39±28.90 pg/mg; p = 0.1267). Conclusion Ghrelin inhibits the inflammatory response and apoptosis during transplant-related IRI. This study demonstrates the protective effects of ghrelin in IRI following HCHT. A further study is warranted to investigate its long-term effects on donor hearts.