New Strategy of Endothelial Protection in Cardiac Surgery: Use of Enhancer of Endothelial Nitric Oxide Synthase

Hong-Mei Xue; Guo-Wei He; Jun-Hao Huang; Qin Yang
July 2010
World Journal of Surgery;Jul2010, Vol. 34 Issue 7, p1461
Academic Journal
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. Porcine coronary small arteries (600–800-μm diameter) were subjected to hypoxia (PO2 <5 mmHg) in St. Thomas cardioplegic (ST) solution with or without AVE3085 (10 μM) or L-arginine (10 mM) at either 37 or 4°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 U46619 precontraction before and after H-R. Protein expressions of eNOS and phosphorylated eNOS at Ser-1177 (p-eNOSSer1177) were also determined. Exposure to ST solution with H-R at both 37 and 4°C markedly reduced bradykinin-induced relaxation in coronary small arteries. Addition of AVE3085 in ST solution at 37°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-eNOSSer1177 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°C. 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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