GHRELIN INHIBITS INFLAMMATORY RESPONSE AND APOPTOSIS DURING ISCHEMIA-REPERFUSION INJURY FOLLOWING A MURINE HEART TRANSPLANTATION MODEL
CCC ePoster Library. Fukunaga N. 10/26/19; 280540; 305
Dr. Naoto Fukunaga
Dr. Naoto Fukunaga
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Abstract
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BACKGROUND: Ischemia-reperfusion injury (IRI) during heart transplantation is a multi-factorial inflammatory condition and an important risk factor for cardiac allograft vasculopathy, which is one of the leading causes of death beyond the first year after transplantation. Ghrelin, a novel growth hormone-releasing peptide discovered in the stomach of rats, has both anti-inflammatory and anti-apoptotic effects on human endothelial cells. In this study, we evaluated the protective effects of ghrelin against IRI following a murine heterotopic cervical heart transplantation (HCHT).

METHODS AND RESULTS: Donor hearts of C57BL/6J mice, which were kept in cold saline for 60 minutes were heterotopically transplanted into C57BL/6J recipients. A day prior to HCHT, donor animals were randomly assigned to receive either ghrelin (300 nmol/kg) or saline (0.3ml) intraperitoneally. Upon reperfusion and on postoperative day 1, either ghrelin or saline was administered. Donor hearts were procured on postoperative day 2 for analysis. 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. TUNEL-positive cells were significantly decreased in the ghrelin group (0.38±0.21% vs. 5.74±3.68%; p < 0.001). Correlating with this, both cleaved caspase-3 activity and Bcl-2/Bax ratio from the ghrelin group were significantly reduced compared to those in the control (p = 0.029 and 0.021, respectively). Furthermore, pAkt/Akt ratio was higher in the ghrelin group (0.44±0.21 vs. 0.14±0.03; p = 0.043). NF-kB p65 nuclear translocation was reduced in the ghrelin hearts compared to the controls (3.17±1.84 % vs. 19.28±13.14 %; p = 0.009). VCAM-1 (p = 0.032), ICAM-1 (p = 0.048), NF-kB (p = 0.013) and TNF-a (p = 0.016) levels were also significantly reduced in the ghrelin-treated group. No significant difference was observed in 8-isoprostane production between groups (47.67±13.14 pg/mg vs. 95.39±28.90 pg/mg; p = 0.127).

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.
BACKGROUND: Ischemia-reperfusion injury (IRI) during heart transplantation is a multi-factorial inflammatory condition and an important risk factor for cardiac allograft vasculopathy, which is one of the leading causes of death beyond the first year after transplantation. Ghrelin, a novel growth hormone-releasing peptide discovered in the stomach of rats, has both anti-inflammatory and anti-apoptotic effects on human endothelial cells. In this study, we evaluated the protective effects of ghrelin against IRI following a murine heterotopic cervical heart transplantation (HCHT).

METHODS AND RESULTS: Donor hearts of C57BL/6J mice, which were kept in cold saline for 60 minutes were heterotopically transplanted into C57BL/6J recipients. A day prior to HCHT, donor animals were randomly assigned to receive either ghrelin (300 nmol/kg) or saline (0.3ml) intraperitoneally. Upon reperfusion and on postoperative day 1, either ghrelin or saline was administered. Donor hearts were procured on postoperative day 2 for analysis. 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. TUNEL-positive cells were significantly decreased in the ghrelin group (0.38±0.21% vs. 5.74±3.68%; p < 0.001). Correlating with this, both cleaved caspase-3 activity and Bcl-2/Bax ratio from the ghrelin group were significantly reduced compared to those in the control (p = 0.029 and 0.021, respectively). Furthermore, pAkt/Akt ratio was higher in the ghrelin group (0.44±0.21 vs. 0.14±0.03; p = 0.043). NF-kB p65 nuclear translocation was reduced in the ghrelin hearts compared to the controls (3.17±1.84 % vs. 19.28±13.14 %; p = 0.009). VCAM-1 (p = 0.032), ICAM-1 (p = 0.048), NF-kB (p = 0.013) and TNF-a (p = 0.016) levels were also significantly reduced in the ghrelin-treated group. No significant difference was observed in 8-isoprostane production between groups (47.67±13.14 pg/mg vs. 95.39±28.90 pg/mg; p = 0.127).

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.
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