Hong-Mei Xue1, Guo-Wei He, Jun-Hao Huang, Qin Yang. 1. Department of Surgery, The Chinese University of Hong Kong, Block B, 5A, Prince of Wales Hospital, Shatin, NT, Hong Kong SAR, China.
Abstract
BACKGROUND: Endothelial dysfunction related to the loss of nitric oxide (NO) production remains an important issue in cardiac surgery. We examined the hypothesis that AVE3085, a novel compound that enhances eNOS transcription, may protect coronary endothelium against hypoxia-reoxygenation (H-R) injury during cardioplegic arrest and the possible mechanism by which this occurs. METHODS: Porcine coronary small arteries (600-800-microm diameter) were subjected to hypoxia (PO(2) <5 mmHg) in St. Thomas cardioplegic (ST) solution with or without AVE3085 (10 microM) or L-arginine (10 mM) at either 37 or 4 degrees C for 60 min, followed by 30-min reoxygenation. Bradykinin (-10 to -6.5 LogM)-induced, endothelium-dependent relaxation was studied in a myograph in U(46619) precontraction before and after H-R. Protein expressions of eNOS and phosphorylated eNOS at Ser-1177 (p-eNOS(Ser1177)) were also determined. RESULTS: Exposure to ST solution with H-R at both 37 and 4 degrees C markedly reduced bradykinin-induced relaxation in coronary small arteries. Addition of AVE3085 in ST solution at 37 degrees C preserved the vasorelaxant response to bradykinin (95.7 +/- 2.1% vs. 69.2 +/- 6.6%, p < 0.01), with the protective effect comparable to that of L-arginine (96.1 +/- 3.3% vs. 70.6 +/- 8.7%, p < 0.05). eNOS and p-eNOS(Ser1177) expressions in coronary endothelial cells were significantly increased by the addition of AVE3085 in ST solution during hypoxia (p < 0.05). Protection of endothelium-dependent relaxation from H-R by AVE3085 (70.3 +/- 7.2% vs. 90.5 +/- 2.4%, p < 0.05) also reached a level similar to that by L-arginine (69.9 +/- 9.0% vs. 94.7 +/- 3.9%, p < 0.05) at 4 degrees C. CONCLUSIONS: We have demonstrated a new mechanism to protect coronary endothelium from H-R injury by using eNOS enhancers. This may form a new strategy in the future development of cardioplegic/preservation solutions with direct targeting of eNOS expression in coronary vasculature.
BACKGROUND: Endothelial dysfunction related to the loss of nitric oxide (NO) production remains an important issue in cardiac surgery. We examined the hypothesis that AVE3085, a novel compound that enhances eNOS transcription, may protect coronary endothelium against hypoxia-reoxygenation (H-R) injury during cardioplegic arrest and the possible mechanism by which this occurs. METHODS: Porcine coronary small arteries (600-800-microm diameter) were subjected to hypoxia (PO(2) <5 mmHg) in St. Thomas cardioplegic (ST) solution with or without AVE3085 (10 microM) or L-arginine (10 mM) at either 37 or 4 degrees C for 60 min, followed by 30-min reoxygenation. Bradykinin (-10 to -6.5 LogM)-induced, endothelium-dependent relaxation was studied in a myograph in U(46619) precontraction before and after H-R. Protein expressions of eNOS and phosphorylated eNOS at Ser-1177 (p-eNOS(Ser1177)) were also determined. RESULTS: Exposure to ST solution with H-R at both 37 and 4 degrees C markedly reduced bradykinin-induced relaxation in coronary small arteries. Addition of AVE3085 in ST solution at 37 degrees C preserved the vasorelaxant response to bradykinin (95.7 +/- 2.1% vs. 69.2 +/- 6.6%, p < 0.01), with the protective effect comparable to that of L-arginine (96.1 +/- 3.3% vs. 70.6 +/- 8.7%, p < 0.05). eNOS and p-eNOS(Ser1177) expressions in coronary endothelial cells were significantly increased by the addition of AVE3085 in ST solution during hypoxia (p < 0.05). Protection of endothelium-dependent relaxation from H-R by AVE3085 (70.3 +/- 7.2% vs. 90.5 +/- 2.4%, p < 0.05) also reached a level similar to that by L-arginine (69.9 +/- 9.0% vs. 94.7 +/- 3.9%, p < 0.05) at 4 degrees C. CONCLUSIONS: We have demonstrated a new mechanism to protect coronary endothelium from H-R injury by using eNOS enhancers. This may form a new strategy in the future development of cardioplegic/preservation solutions with direct targeting of eNOS expression in coronary vasculature.
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