氨基脲敏感型胺氧化酶在心肌缺血再灌注中的作用
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摘要
氨基脲敏感型胺氧化酶(Semicarbazide-sensitive amine oxidase, SSAO; EC1.4.3.6)是一组含铜胺氧化酶的统称,广泛分布于器官和组织中,尤其在脂肪细胞、血管内皮细胞和平滑肌细胞中酶活性较高,它的可溶性形式也存在于血浆中。脂肪细胞和平滑肌细胞表达的SSAO酶可促进葡萄糖转运,具有类胰岛素效应;而内皮细胞表达的SSAO酶即血管黏附蛋白-1(VAP-1)参与炎症过程中白细胞的运输与外渗。生化方面,SSAO催化伯胺的氧化脱胺生成相应的醛、氨和过氧化氢(RCH2NH2 + O2 + H2O→RCHO + NH3 + H2O2)。有研究表明在离体肺缺血再灌注损伤模型中SSAO参与过多活性氧族的生成。然而SSAO在心肌缺血再灌注损伤中是否起作用尚未见报道。因此,我们用大鼠缺血再灌注模型来验证这一假设。
所有SD大鼠心脏都给予缺血30 min再灌注180 min的处理。所有大鼠随机分成八组,每组十只:
1)缺血再灌注对照组:缺血前后不给予任何干预;
2)氨基脲处理组:实验前10 min给予氨基脲(30 mg/kg,溶解于1 ml生理盐水)处理;
3)缺血预适应组:长时间缺血前给予5 min缺血10 min再灌注;
4)缺血预适应+氨基脲处理组:实验前10 min给予氨基脲处理,然后长时间缺血前给予5 min缺血10 min再灌注;
5)缺血后适应组:长时间再灌注前给予3个循环10 s再灌注和10 s再缺血的后处理。
6)缺血后适应+氨基脲处理组:实验前10 min给予氨基脲处理,然后长时间再灌注前给予3个循环10 s再灌注和10 s再缺血的后处理。
7)假手术组:实验过程同其他组,但穿线不结扎。
8)假手术+氨基脲处理组:实验前10 min给予氨基脲处理,然后穿线不结扎。
在本实验中,采用NBT(氯化硝基四氮唑兰)染色法测定心肌梗塞范围;比色法测定大鼠血浆肌酸激酶(CK)、丙二醛(MDA)、髓过氧化物酶(MPO)、羟自由基(·OH)等水平;高效液相色谱法测定血浆SSAO酶活性;HE染色法进行组织学评估。
在本实验中我们得到如下结果:
(1)各组的心肌梗塞范围为:缺血再灌注对照组(43.2±1.0%);氨基脲处理组(27.7±1.2%);缺血预适应组(29.3±2.2%);缺血预适应+氨基脲处理组(13.9±3.2%);缺血后适应组(33.6±1.9%);缺血后适应+氨基脲处理组(41.1±4.2%)。与缺血再灌注对照组相比,除了缺血后适应+氨基脲处理组没有统计学差异外,其他组均有统计学差异。
(2)各组血浆肌酸激酶活力(U/ml)为:缺血再灌注对照组(2.83±0.33);氨基脲处理组(2.64±0.26);缺血预适应组(2.22±0.25);缺血预适应+氨基脲处理组(2.51±0.32);缺血后适应组(2.28±0.40);缺血后适应+氨基脲处理组(2.61±0.26);假手术组(2.26±0.40);假手术+氨基脲处理组(2.28±0.28)。各组之间没有统计学差异。
(3)各组血浆丙二醛水平(nmol/ml)为:缺血再灌注对照组(2.58±0.14);氨基脲处理组(1.74±0.16);缺血预适应组(2.13±0.15);缺血预适应+氨基脲处理组(1.78±0.06);缺血后适应组(2.47±0.21);缺血后适应+氨基脲处理组(1.77±0.17);假手术组(2.11±0.12);假手术+氨基脲处理组(1.66±0.10)。与缺血再灌注对照组相比,所有氨基脲处理组血浆丙二醛水平都显著降低了;与缺血后适应组相比,所有氨基脲处理组血浆丙二醛水平也显著降低。
(4)各组血浆髓过氧化物酶活性(U/L)为:缺血再灌注对照组(27.53±2.93);氨基脲处理组(14.16±1.78);缺血预适应组(14.16±1.85);缺血预适应+氨基脲处理组(13.37±1.49);缺血后适应组(13.57±2.56);缺血后适应+氨基脲处理组(12.39±1.63);假手术组(13.18±2.23);假手术+氨基脲处理组(17.90±2.61)。与缺血再灌注对照组相比,其他组血浆髓过氧化物酶活性都显著降低。
(5)各组血浆羟自由基水平(U/ml)为:缺血再灌注对照组(628.4±15.7);氨基脲处理组(502.6±27.8);缺血预适应组(509.6±29.9);缺血预适应+氨基脲处理组(505.4±26.9);缺血后适应组(526.6±16.8);缺血后适应+氨基脲处理组(496.9±32.6);假手术组(502.8±25.7);假手术+氨基脲处理组(525.7±29.8)。与缺血再灌注对照组相比,其他组血浆羟自由基水平都显著降低。
(6)HE染色结果表明抑制SSAO酶活性显著减少了白细胞的聚集。总之,我们的研究表明抑制SSAO酶可以缓解心肌缺血再灌注损伤。
Semicarbazide-sensitive amine oxidase (SSAO, EC1.4.3.6) is a common name for a group of copper-containing amine oxidases widely distributed in organs and tissues, especially in adipocytes, endothelial and smooth muscle cells. Soluble form of SSAO is also present in blood plasma. In adipocytes and smooth muscle cells, SSAO activity stimulates glucose transport, mimicking the insulin effect, while in endothelial cells, where it is identical to vascular adhesion protein-1 (VAP-1), it is involved in leukocyte trafficking and extravasation during inflammation. Biochemically, SSAO catalyzes the oxidative deamination of primary amines to produce aldehydes, ammonia, and hydrogen peroxide (RCH2NH2 + O2 + H2O→RCHO + NH3 + H2O2). Previous studies have shown that SSAO contributes to the excessive ROS formation in the isolated rat lung with ischemia-reperfusion injury. However, it remains unclear whether inhibition of SSAO plays a role in the regulation of myocardial ischemia-reperfusion injury. Therefore, we used an open-chest rat model of left coronary artery occlusion and reperfusion to test the hypothesis whether inhibition of SSAO would attenuate reperfusion-induced myocardial injury.
In anesthetized open-chest Sprague-Dawley rats, the left coronary artery (LCA) underwent 30 min ischemia and 180 min reperfusion (R). All rats were randomly divided into eight groups, each group consists of 10 animals:
(1) Control: There was no intervention either before or after the prolonged occlusion;
(2) Semicarbazide (Sem): Sem (30 mg/kg, dissolved in saline as a volume of 1 ml/kg), a selective SSAO inhibitor, was given 10 min prior to the experiment;
(3) Ischemia preconditioning (pre-con): 5 min ischemia followed by 10 min R before the prolonged occlusion;
(4) Pre-con + Sem: Sem was given 10 min prior to the experiment, 5 min ischemia then 10 min R before the prolonged occlusion;
(5) Ischemia postconditioning (post-con): 3 cycles of 10 s R and 10 s re-ischemia prior to 180 min R;
(6) Post-con + Sem: Sem was given 10 min prior to the experiment, and 3 cycles of 10 s R and 10 s re-ischemia prior to 180 min R;
(7) Sham: the surgical procedure was identical to other groups, but the LCA ligature was not ligated;
(8) Sham + Sem: Sem was given 10 min prior to the experiment, and the LCA ligature was not ligated.
In this experiment, the NBT staining was used to determine myocardial infarct size; colorimetric method was used to determine plasma creatine kinase (CK) activity, plasma malondialdehyde (MDA) levels, plasma myeloperoxidase (MPO) activity, and plasma hydroxyl radicals levels; plasma SSAO activity was measured by high performance liquid chromatography (HPLC); the HE staining was used to make a histological evalution.
Infarct sizes in Sem-treated group (27.7±1.2%), pre-con group (29.3±2.2%), pre-con + Sem group (13.9±3.2%) and post-con group (33.6±1.9%) were remarkably smaller than control group (43.2±1.0%). Post-con + Sem group (41.1±4.2%) showed no difference with control.
Plasma CK activity (U/ml) in different groups were 2.83±0.33 (control group), 2.64±0.26 (Sem-treated group), 2.22±0.25 (pre-con group), 2.51±0.32 (pre-con + Sem group), 2.28±0.40 (post-con group), 2.61±0.26 (post-con + Sem group), 2.26±0.40 (sham group), 2.28±0.28 (sham + Sem group). There were no significant differences among all the groups.
Plasma MDA levels (nmol/ml) were significantly reduced in the Sem-treated group (1.74±0.16), pre-con + Sem group (1.78±0.06), post-con + Sem group (1.77±0.17), sham + sem group (1.66±0.10) compared with control group (2.58±0.14) or post-con group(2.47±0.21). Plasma MPO activity (U/L) was found to be significantly decreased in the sem-treated group (14.16±1.78), pre-con group (14.16±1.85), pre-con + sem group (13.37±1.49), post-con group (13.57±2.56), post-con + sem group (12.39±1.63), sham group (13.18±2.23) and sham + sem group (17.90±2.61) compared with control group (27.53±2.93).
Plasma hydroxyl radicals levels (U/ml) were significantly less in the sem-treated group (502.6±27.8), pre-con group (509.6±29.9), pre-con + sem group (505.4±26.9), post-con group (526.6±16.8), post-con + sem group (496.9±32.6), sham group (502.8±25.7) and sham + sem group (525.7±29.8) compared with control group (628.4±15.7).
The results of HE staining showed that inhibition of SSAO significantly attenuated leukocyte infiltration.
In conclusion, this study demonstrated that inhibition of SSAO protects the ischemic heart against myocardial ischemia-reperfusion injury.
所有SD大鼠心脏都给予缺血30 min再灌注180 min的处理。所有大鼠随机分成八组,每组十只:
1)缺血再灌注对照组:缺血前后不给予任何干预;
2)氨基脲处理组:实验前10 min给予氨基脲(30 mg/kg,溶解于1 ml生理盐水)处理;
3)缺血预适应组:长时间缺血前给予5 min缺血10 min再灌注;
4)缺血预适应+氨基脲处理组:实验前10 min给予氨基脲处理,然后长时间缺血前给予5 min缺血10 min再灌注;
5)缺血后适应组:长时间再灌注前给予3个循环10 s再灌注和10 s再缺血的后处理。
6)缺血后适应+氨基脲处理组:实验前10 min给予氨基脲处理,然后长时间再灌注前给予3个循环10 s再灌注和10 s再缺血的后处理。
7)假手术组:实验过程同其他组,但穿线不结扎。
8)假手术+氨基脲处理组:实验前10 min给予氨基脲处理,然后穿线不结扎。
在本实验中,采用NBT(氯化硝基四氮唑兰)染色法测定心肌梗塞范围;比色法测定大鼠血浆肌酸激酶(CK)、丙二醛(MDA)、髓过氧化物酶(MPO)、羟自由基(·OH)等水平;高效液相色谱法测定血浆SSAO酶活性;HE染色法进行组织学评估。
在本实验中我们得到如下结果:
(1)各组的心肌梗塞范围为:缺血再灌注对照组(43.2±1.0%);氨基脲处理组(27.7±1.2%);缺血预适应组(29.3±2.2%);缺血预适应+氨基脲处理组(13.9±3.2%);缺血后适应组(33.6±1.9%);缺血后适应+氨基脲处理组(41.1±4.2%)。与缺血再灌注对照组相比,除了缺血后适应+氨基脲处理组没有统计学差异外,其他组均有统计学差异。
(2)各组血浆肌酸激酶活力(U/ml)为:缺血再灌注对照组(2.83±0.33);氨基脲处理组(2.64±0.26);缺血预适应组(2.22±0.25);缺血预适应+氨基脲处理组(2.51±0.32);缺血后适应组(2.28±0.40);缺血后适应+氨基脲处理组(2.61±0.26);假手术组(2.26±0.40);假手术+氨基脲处理组(2.28±0.28)。各组之间没有统计学差异。
(3)各组血浆丙二醛水平(nmol/ml)为:缺血再灌注对照组(2.58±0.14);氨基脲处理组(1.74±0.16);缺血预适应组(2.13±0.15);缺血预适应+氨基脲处理组(1.78±0.06);缺血后适应组(2.47±0.21);缺血后适应+氨基脲处理组(1.77±0.17);假手术组(2.11±0.12);假手术+氨基脲处理组(1.66±0.10)。与缺血再灌注对照组相比,所有氨基脲处理组血浆丙二醛水平都显著降低了;与缺血后适应组相比,所有氨基脲处理组血浆丙二醛水平也显著降低。
(4)各组血浆髓过氧化物酶活性(U/L)为:缺血再灌注对照组(27.53±2.93);氨基脲处理组(14.16±1.78);缺血预适应组(14.16±1.85);缺血预适应+氨基脲处理组(13.37±1.49);缺血后适应组(13.57±2.56);缺血后适应+氨基脲处理组(12.39±1.63);假手术组(13.18±2.23);假手术+氨基脲处理组(17.90±2.61)。与缺血再灌注对照组相比,其他组血浆髓过氧化物酶活性都显著降低。
(5)各组血浆羟自由基水平(U/ml)为:缺血再灌注对照组(628.4±15.7);氨基脲处理组(502.6±27.8);缺血预适应组(509.6±29.9);缺血预适应+氨基脲处理组(505.4±26.9);缺血后适应组(526.6±16.8);缺血后适应+氨基脲处理组(496.9±32.6);假手术组(502.8±25.7);假手术+氨基脲处理组(525.7±29.8)。与缺血再灌注对照组相比,其他组血浆羟自由基水平都显著降低。
(6)HE染色结果表明抑制SSAO酶活性显著减少了白细胞的聚集。总之,我们的研究表明抑制SSAO酶可以缓解心肌缺血再灌注损伤。
Semicarbazide-sensitive amine oxidase (SSAO, EC1.4.3.6) is a common name for a group of copper-containing amine oxidases widely distributed in organs and tissues, especially in adipocytes, endothelial and smooth muscle cells. Soluble form of SSAO is also present in blood plasma. In adipocytes and smooth muscle cells, SSAO activity stimulates glucose transport, mimicking the insulin effect, while in endothelial cells, where it is identical to vascular adhesion protein-1 (VAP-1), it is involved in leukocyte trafficking and extravasation during inflammation. Biochemically, SSAO catalyzes the oxidative deamination of primary amines to produce aldehydes, ammonia, and hydrogen peroxide (RCH2NH2 + O2 + H2O→RCHO + NH3 + H2O2). Previous studies have shown that SSAO contributes to the excessive ROS formation in the isolated rat lung with ischemia-reperfusion injury. However, it remains unclear whether inhibition of SSAO plays a role in the regulation of myocardial ischemia-reperfusion injury. Therefore, we used an open-chest rat model of left coronary artery occlusion and reperfusion to test the hypothesis whether inhibition of SSAO would attenuate reperfusion-induced myocardial injury.
In anesthetized open-chest Sprague-Dawley rats, the left coronary artery (LCA) underwent 30 min ischemia and 180 min reperfusion (R). All rats were randomly divided into eight groups, each group consists of 10 animals:
(1) Control: There was no intervention either before or after the prolonged occlusion;
(2) Semicarbazide (Sem): Sem (30 mg/kg, dissolved in saline as a volume of 1 ml/kg), a selective SSAO inhibitor, was given 10 min prior to the experiment;
(3) Ischemia preconditioning (pre-con): 5 min ischemia followed by 10 min R before the prolonged occlusion;
(4) Pre-con + Sem: Sem was given 10 min prior to the experiment, 5 min ischemia then 10 min R before the prolonged occlusion;
(5) Ischemia postconditioning (post-con): 3 cycles of 10 s R and 10 s re-ischemia prior to 180 min R;
(6) Post-con + Sem: Sem was given 10 min prior to the experiment, and 3 cycles of 10 s R and 10 s re-ischemia prior to 180 min R;
(7) Sham: the surgical procedure was identical to other groups, but the LCA ligature was not ligated;
(8) Sham + Sem: Sem was given 10 min prior to the experiment, and the LCA ligature was not ligated.
In this experiment, the NBT staining was used to determine myocardial infarct size; colorimetric method was used to determine plasma creatine kinase (CK) activity, plasma malondialdehyde (MDA) levels, plasma myeloperoxidase (MPO) activity, and plasma hydroxyl radicals levels; plasma SSAO activity was measured by high performance liquid chromatography (HPLC); the HE staining was used to make a histological evalution.
Infarct sizes in Sem-treated group (27.7±1.2%), pre-con group (29.3±2.2%), pre-con + Sem group (13.9±3.2%) and post-con group (33.6±1.9%) were remarkably smaller than control group (43.2±1.0%). Post-con + Sem group (41.1±4.2%) showed no difference with control.
Plasma CK activity (U/ml) in different groups were 2.83±0.33 (control group), 2.64±0.26 (Sem-treated group), 2.22±0.25 (pre-con group), 2.51±0.32 (pre-con + Sem group), 2.28±0.40 (post-con group), 2.61±0.26 (post-con + Sem group), 2.26±0.40 (sham group), 2.28±0.28 (sham + Sem group). There were no significant differences among all the groups.
Plasma MDA levels (nmol/ml) were significantly reduced in the Sem-treated group (1.74±0.16), pre-con + Sem group (1.78±0.06), post-con + Sem group (1.77±0.17), sham + sem group (1.66±0.10) compared with control group (2.58±0.14) or post-con group(2.47±0.21). Plasma MPO activity (U/L) was found to be significantly decreased in the sem-treated group (14.16±1.78), pre-con group (14.16±1.85), pre-con + sem group (13.37±1.49), post-con group (13.57±2.56), post-con + sem group (12.39±1.63), sham group (13.18±2.23) and sham + sem group (17.90±2.61) compared with control group (27.53±2.93).
Plasma hydroxyl radicals levels (U/ml) were significantly less in the sem-treated group (502.6±27.8), pre-con group (509.6±29.9), pre-con + sem group (505.4±26.9), post-con group (526.6±16.8), post-con + sem group (496.9±32.6), sham group (502.8±25.7) and sham + sem group (525.7±29.8) compared with control group (628.4±15.7).
The results of HE staining showed that inhibition of SSAO significantly attenuated leukocyte infiltration.
In conclusion, this study demonstrated that inhibition of SSAO protects the ischemic heart against myocardial ischemia-reperfusion injury.
引文
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16. Jalkanen S, Karikoski M, Mercier N, Koskinen K, Henttinen T, Elima K, Salmivirta K, Salmi M. The oxidase activity of vascular adhesion protein-1 (VAP-1) induces endothelial E- and P-selectins and leukocyte binding. Blood 2007;110:1864-1870.
17. O’Sullivan J, Unzeta M, Healy J, O’Sullivan MI, Davey G, Tipton KF. Semicarbazide-sensitive amine oxidases: enzymes with quite a lot to do. Neurotoxicology 2004;25:303-315.
18. Deng Y, Boomsma F, Yu PH. Deamination of methylamine and aminoacetone increases aldehydes and oxidative stress in rats. Life Sci 1998;63:2049-2058.
19. Lichszteld K, Kruk I. Singlet molecular oxygen in formaldehyde oxidation. Z Phys Chem 1977;108:167-172.
20. Ucar G, Topaloglu E, Burak Kandilci H, Gumusel B. Elevated semicarbazide-sensitive amine oxidase (SSAO) activity in lung with ischemia-reperfusion injury: protective effect of ischemic preconditioning plus SSAO inhibition. Life Sci 2005;78:421-427.
21. Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 2003;285:579-588.
22. Kin H, Zhao ZQ, Sun HY, Wang NP, Corvera JS, Halkos ME, Kerendi F, Guyton RA, Vinten-Johansen J. Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion. Cardiovasc Res 2004;62:74-85.
23. Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L'Huillier I, Aupetit JF, Bonnefoy E, Finet G, André-Fou?t X, Ovize M. Postconditioning the human heart. Circulation2005;112:2143-2148.
24. Hausenloy DJ, Yellon DM. Preconditioning and postconditioning: united at reperfusion. Pharmacol Ther 2007;116:173-191.
25. Zhao TC, Cheng G, Zhang LX, Tseng YT, Padbury JF. Inhibition of histone deacetylases triggers pharmacologic preconditioning effects against myocardial ischemic injury. Cardiovasc Res 2007;76:473-481.
26. Kloner RA, Rezkalla SH. Preconditioning, postconditioning and their application to clinical cardiology. Cardiovasc Res 2006;70:297-307.
27. Roberts AJ, Cipriano PR, Alonso DR, Jacbostein JG, Combes JR, Gay WA Jr. Evaluation of methods for the quantification of experimental myocardial infarction. Circulation 1978;57:35-41.
28. Li H, Luo WH, Lin JJ, Lin Z, Zhang Y. Assay of plasma semicarbazide-sensitive amine oxidase and determination of its endogenous substrate methylamine by liquid chromatography. J Chromatogr B 2004;810:277-282.
29. Paradies G, Petrosillo G, Pistolese M, Venosa ND, Serena D, Ruggiero FM. Lipid peroxidation and alterations to oxidative metabolism in mitochondria isolated from rat heart subjected to ischemia and reperfusion. Free Radical Biol Med 1999;27:42-50.
30. Ambrosio G, Flaherty JT, Duilio C, Tritto I, Santoro G, Elia PP, Condorelli M, Chiariello M. Oxygen radicals generated at reflow induce peroxidation of membrane lipids in reperfused hearts. J Clin Invest 1991;87:2056-2066.
31. Nicholls SJ, Hazen SL. Myeloperoxidase and cardiovascular disease. Arterioscler Thromb Vasc Biol 2005;25:1102-1111.
32. Brennan ML, Penn MS, Van Lente F, Nambi V, Shishehbor MH, Aviles RJ, Goormastic M, Pepoy ML, McErlean ES, Topol EJ, Nissen SE, Hazen SL. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med 2003;349:1595-1604.
33. Kinemuchi H, Sugimoto H, Obata T, Satoh N, Ueda S. Selective inhibitors of membrane-bound semicarbazide-sensitive amine oxidase (SSAO) activity in mammalian tissues. NeuroToxicology 2004;25:325-335.
34. Conklin DJ, Cowley HR, Wiechmann RJ, Johnson GH, Trent MB, Boor PJ. Vasoactive effects of methylamine in isolated human blood vessels: role of semicarbazide-sensitive amine oxidase, formaldehyde, and hydrogen peroxide. Am J Physiol Heart Circ Physiol 2004;286:667-673.
35. Jaakkola K, Jalkanen S, Kaunism?ki K, V?nttinen E, Saukko P, Alanen K, Kallajoki M, Voipio-Pulkki LM, Salmi M. Vascular adhesion protein-1, intercellular adhesion molecule-1and P-selectin mediate leukocyte binding to ischemic heart in humans. J AM Coll Cardiol 2000;36:122-129.
36. Xu HL, Salter-Cid L, Linnik MD, Wang EY, Paisansathan C, Pelligrino DA. Vascular adhesion protein-1 plays an important role in postischemic inflammation and neuropathology in diabetic, estrogen-treated ovariectomized female rats subjected to transient forebrain ischemia. J Pharmacol Exp Ther 2006;317:19-29.
37. Kiss J, Jalkanen S, Fül?p F, Savunen T, Salmi M. Ischemia-reperfusion injury is attenuated in VAP-1-deficient mice and by VAP-1 inhibitors. Eur J Immunol 2008;38:3041-3049.
38. Tsutsumi YM, Yokoyama T, Horikama Y, Roth DM, Patel HH. Reactive oxygen species trigger ischemic and pharmacological postconditioning: in vivo and in vitro characterization. Life Sci 2007;81:1223-1227.
39. Vidrio H, Medina M. Hypotensive effect of hydroxylamine, an endogenous nitric oxide donor and SSAO inhibitor. J Neural Transm 2007;114:863-865.
40. Salter-Cid LM, Wang E, O'Rourke AM, Miller A, Gao H, Huang L, Garcia A, Linnik MD. Anti-inflammatory effects of inhibiting the amine oxidase activity of semicarbazide-sensitive amine oxidase. J Pharmacol Exp Ther 2005;315:553-562.
41. Wang EY, Gao H, Salter-Cid L, Zhang J, Huang L, Podar EM, Miller A, Zhao J, O'rourke A, Linnik MD. Design, synthesis, and biological evaluation of semicarbazide-sensitive amine oxidase (SSAO) inhibitors with anti-inflammatory activity. J Med Chem 2006;49:2166-2173.
42. O'Rourke AM, Wang EY, Miller A, Podar EM, Scheyhing K, Huang L, Kessler C, Gao H, Ton-Nu HT, Macdonald MT, Jones DS, Linnik MD. Anti-inflammatory effects of LJP 1586 [Z-3-fluoro-2-(4-methoxybenzyl)allylamine hydrochloride], an amine-based inhibitor of semicarbazide-sensitive amine oxidase activity. J Pharmacol Exp Ther 2008;324:867-875.
1. Andres N, Lizcano JM, Rodriguez MJ, Romera M, Unzeta M, Mahy N. Tissue Activity and Cellular Localization of Human Semicarbazide-sensitive Amine Oxidase. J Histochem. Cytochem 2001;49:209-217.
2. Enrique-Tarancón G, Castan I, Morin N, Marti L, Abella A, Camps M, Casamitjana R, Palacín M, Testar X, Degerman E, CarpénéC, Zorzano A. Substrates of semicarbazide-sensitive amine oxidase co-operate with vanadate to stimulate tyrosine phosphorylation of insulin-receptor-substrate proteins, phosphoinositide 3-kinase activity and GLUT4 translocation in adipose cells. Biochem J 2000;350:171-180.
3. Enrique-Tarancón G, Marti L, Morin N, Lizcano JM, Unzeta M, Sevilla L, Camps M, Palacín M, Testar X, CarpénéC, Zorzano A. Role of semicarbazide-sensitive amine oxidase on glucose transport and GLUT4 recruitment to the cell surface in adipose cells. J Biol Chem 1998;273:8025-8032.
4. El Hadri K, Moldes M, Mercier N, Andreani M, Pairault J, Feve B. Semicarbazide-sensitive amine oxidase in vascular smooth muscle cells: differentiation-dependent expression and role in glucose uptake. Arterioscler Thromb Vasc Biol 2002;22:89-94.
5. Stolen CM, Yegutkin GG, Kurkij?rvi R, Bono P, Alitalo K, Jalkanen S. Origins of serum semicarbazide-sensitive amine oxidase. Circ Res 2004;95:50-57.
6. Lyles GA. Mammalian plasma and tissue-bound semicarbazide-sensitive amine oxidases: biochemical, pharmacological and toxicological aspects. Int J Biochem Cell Biol 1996;28:259-274.
7. Stolen CM, Madanat R, Marti L, Kari S, Yegutkin GG, Sariola H, Zorzano A, Jalkanen S. Semicarbazide-sensitive amine oxidase overexpression has dual consequences: insulin mimicry and diabetes-like complications. FASEB J 2004;18:702-704.
8. Bono P, Salmi M, Smith DJ, Jalkanen S. Cloning and characterization of mouse vascular adhesion protein-1 reveals a novel molecule with enzymatic activity. J Immunol 1998;160:5563-5571.
9. Smith DJ, Salmi M, Bono P, Hellman J, Leu T, Jalkanen S. Cloning of vascular adhesion protein 1 reveals a novel multifunctional adhesion molecule. J Exp Med 1998;188:17-27.
10. Salmi M, Jalkanen S. VAP-1: an adhesion and an enzyme. Trends Immunol 2001;22:211-216.
11. Tohka S, Laukkanen M, Jalkanen S, Salmi M. Vascular adhesion protein-1(VAP-1)functions as a molecular brake during granulocyte rolling and mediates recruitment in vivo. FASEB J 2001;15:373-382.
12. Salmi M, Yegutkin GG, Lehvonen R, Koskinen K, Salminen T, Jalkanen S. A cell surface amine oxidase directly controls lymphocyte migration. Immunity 2001;14:265-276.
13. Koskinen K, Vainio PJ, Smith DJ, Pihlavisto M, Yl?-Herttuala S, Jalkanen S, Salmi M. Granulocyte transmigration through the endothelium is regulated by the oxidase activity of vascular adhesion protein-1 (VAP-1). Blood 2004;103:3388-3395.
14. Jalkanen S, Karikoski M, Mercier N, Koskinen K, Henttinen T, Elima K, Salmivirta K, Salmi M. The oxidase activity of vascular adhesion protein-1 (VAP-1) induces endothelial E- and P-selectins and leukocyte binding. Blood 2007;110:1864-1870.
15. Yu PH, Wright S, Fan EH, LUN ZR, Gubisne-Harberle D. Physiological and pathological implications of semicarbazide-sensitive amine oxidase. Biochim Biophys Acta 2003;1647:193-199.
16. O’Sullivan J, Unzeta M, Healy J, O’Sullivan M I, Davey G, Tipton KF. Semicarbazide-Sensitive Amine Oxidases: Enzymes with Quite a Lot to Do. Neurotoxicology 2004;25:303-315.
17. Klinman JP, Mu D. Quinoenzymes in biology. Annu Rev Biochem. 1994;63:299-344.
18. Jalkanen S, Salmi M. Cell surface monoamine oxidases: enzymes in search of a function. EMBO J 2001;20:3893-3901.
19. Schwelberger HG. The origin of mammalian plasma amine oxidases. J Neural Transm 2007;114:757-762.
20. Zhang X, McIntire WS. Cloning and sequencing of a copper-containing, topa quinone-containing monoamine oxidase from human placenta. Gene 1996;179:279-286.
21. Kinemuchi H, Sugimoto H, Obata T, Satoh N, Ueda S. Selective inhibitors of membrane-bound semicarbazide-sensitive amine oxidase (SSAO) activity in mammalian tissues. NeuroToxicology 2004;25:325-335.
22. Deng Y, Boomsma F, Yu PH. Deamination of methylamine and aminoacetone increases aldehydes and oxidative stress in rats. Life Sci 1998;63:2049-2058.
23. Lichszteld K, Kruk I. Singlet molecular oxygen in formaldehyde oxidation. Z Phys Chem 1977;108:167-172.
24. Salmi M, Tohka S, Berg EL, Butcher EC, Jalkanen S. Vascular adhesion protein-1 (VAP-1) mediates lymphocyte subtype-specific, selectin-independent recognition of vascular endothelium in human lymph nodes. J Exp Med 1997;186:589-600.
25. Salmi M, Kalimo K, Jalkanen S. Induction and function of vascular adhesion protein-1 atsites of inflammation. J Exp Med 1993;178:2255-2260.
26. Salmi M, Jalkanen S. A 90-kilodalton endothelial cell molecule mediating lymphocyte binding in humans. Science 1992;257:1407-1409.
27. McNab G, Reeves JL, Salmi M, Hubscher S, Jalkanen S, Adams DH. Vascular adhesion protein-1 mediates binding of T cells to human hepatic endothelium. Gastroenterology 1996;110:522-528.
28. Lalor PF, Edwards S, McNab G, Salmi M, Jalkanen S, Adams DH. Vascular adhesion protein-1 mediates adhesion and transmigration of lymphocytes on human hepatic endothelial cells. J Immunol 2002;169:983-992.
29. Bonder CS, Norman MU, Swain MG, Zbytnuik LD, Yamanouchi J, Santamaria P, Ajuebor M, Salmi M, Jalkanen S, Kubes P.Rules of recruitment for Th1 and Th2 lymphocytes in inflamed liver: a role for alpha-4 integrin and vascular adhesion protein-1. Immunity 2005;23:153-163.
30. Merinen M, Irjala H, Salmi M, Jaakkola I, H?nninen A, Jalkanen S. Vascular adhesion protein-1 is involved in both acute and chronic inflammation in the mouse. Am J Pathol 2005;166:793-800.
31. Lalor PF, Edwards S, McNab G, Salmi M, Jalkanen S, Adams DH. Vascular adhesion protein-1 mediates adhesion and transmigration of lymphocytes on human hepatic endothelial cells. J Immunol 2002;169:983-992.
32. Salmi M, Jalkanen S. Cell-surface enzymes in control of leukocyte trafficking. Nat Rev Immunol 2005;5:760-771.
33. Reth M. Hydrogen peroxide as second messenger in lymphocyte activation. Nat Immunol 2002;3:1129-1134.
34. Johnston B, Kanwar S, Kubes P. Hydrogen peroxide induces leukocyte rolling: modulation by endogenous antioxidant mechanisms including NO. Am J Physiol 1996;271:H614-621.
35. Kurkij?rvi R, Adams DH, Leino R, M?tt?nen T, Jalkanen S, Salmi M. Circulating form of human vascular adhesion protein-1 (VAP-1): increased serum levels in inflammatory liver diseases. J Immunol 1998;161:1549-57.
36. Abella A, García-Vicente S, Viguerie N, Ros-BaróA, Camps M, Palacín M, Zorzano A, Marti L. Adipocytes release a soluble form of VAP-1/SSAO by a metalloprotease-dependent process and in a regulated manner. Diabetologia 2004;47:429-438.
37. G?ktürk C, Nilsson J, Nordquist J, Kristensson M, Svensson K, S?derberg C, Israelson M, Garpenstrand H, Sj?quist M, Oreland L, Forsberg-Nilsson K. Overexpression ofsemicarbazide-sensitive amine oxidase in smooth muscle cells leads to an abnormal structure of the aortic elastic laminas. Am J Pathol 2003;163:1921-1928.
38. Boomsma F, van den Meiracker AH, Winkel S, Aanstoot HJ, Batstra MR, Man in 't Veld AJ, Bruining GJ. Circulating semicarbazide-sensitive amine oxidase is raised both in type I (insulin-dependent), in type II (non-insulin-dependent) diabetes mellitus and even in childhood type I diabetes at first clinical diagnosis. Diabetologia 1999;42:233-237.
39. Boomsma F, Derkx FH, van den Meiracker AH, Man in 't Veld AJ, Schalekamp MA. Plasma semicarbazide-sensitive amine oxidase activity is elevated in diabetes mellitus and correlates with glycosylated haemoglobin. Clin Sci 1995;88:675-679.
40. Garpenstrand H, Ekblom J, B?cklund LB, Oreland L, Rosenqvist U. Elevated plasma semicarbazide-sensitive amine oxidase (SSAO) activity in Type 2 diabetes mellitus complicated by retinopathy. Diabetic Med 1999;16:514-521.
41. Mészáros Z, Szombathy T, Raimondi L, Karádi I, Romics L, Magyar K. Elevated serum semicarbazide-sensitive amine oxidase activity in non-insulin-dependent diabetes mellitus: correlation with body mass index and serum triglyceride. Metabolism 1999;48:113-117.
42. Yu PH, Deng YL. Endogenous formaldehyde as a potential factor of vulnerability of atherosclerosis: involvement of semicarbazide-sensitive amine oxidase-mediated methylamine turnover. Atherosclerosis 1998;140:357-363.
43. Boomsma F, de Kam PJ, Tjeerdsma G, van den Meiracker AH, van Veldhuisen DJ. Plasma semicarbazide-sensitive amine oxidase (SSAO) is an independent prognostic marker for mortality in chronic heart failure. Eur Heart J 2000;21:1859-1863.
44. Boomsma F, Bhaggoe UM, van der Houwen AM, van den Meiracker AH. Plasma semicarbazide-sensitive amine oxidase in human (patho)physiology. Biochim Biophys Acta 2003;1647:48-54.
45. Boomsma F, Hut H, Bagghoe U, van der Houwen A, van den Meiracker A. Semicarbazide-sensitive amine oxidase (SSAO): from cell to circulation. Med Sci Monit 2005;11:RA122-126.
46. Gearing AJ, Newman W. Circulating adhesion molecules in disease. Immunol Today 1993;14:506-12.
47. Henriques JP, Gheeraert PJ, Ottervanger JP, de Boer MJ, Dambrink JH, Gosselink AT, van 't Hof AW, Hoorntje JC, Suryapranata H, Zijlstra F. Ventricular fibrillation in acute myocardial infarction before and during primary PCI. Int J Cardiol 2005;105:262-266.
48. Osmancik PP, Stros P, Herman D. In-hospital arrhythmias in patients with acute myocardial infarction - the relation to the reperfusion strategy and their prognostic impact.Acute Card Care 2008;10:15-25.
49. Kang S, Yang Y. Coronary microvascular reperfusion injury and no-reflow in acute myocardial infarction. Clin Invest Med 2007;30:E133-45.
50. Reffelmann T, Kloner RA. Microvascular reperfusion injury: rapid expansion of anatomic no reflow during reperfusion in the rabbit. Am J Physiol Heart Circ Physiol 2002;283:H1099-107.
51. Reffelmann T, Kloner RA. Microvascular alterations after temporary coronary artery occlusion: the no-reflow phenomenon. J Cardiovasc Pharmacol Ther 2004;9:163-72.
52. Ucar G, Topaloglu E, Burak Kandilci H, Gumusel B. Elevated semicarbazide-sensitive amine oxidase (SSAO) activity in lung with ischemia-reperfusion injury: protective effect of ischemic preconditioning plus SSAO inhibition. Life Sci 2005;78:421-427.
53. Xu HL, Salter-Cid L, Linnik MD, Wang EY, Paisansathan C, Pelligrino DA. Vascular adhesion protein-1 plays an important role in postischemic inflammation and neuropathology in diabetic, estrogen-treated ovariectomized female rats subjected to transient forebrain ischemia. J Pharmacol Exp Ther 2006;317:19-29.
54. Kiss J, Jalkanen S, Fül?p F, Savunen T, Salmi M. Ischemia-reperfusion injury is attenuated in VAP-1-deficient mice and by VAP-1 inhibitors. Eur J Immunol 2008;38:3041-3049.
55. O'Rourke AM, Wang EY, Salter-Cid L, Huang L, Miller A, Podar E, Gao HF, Jones DS, Linnik MD. Benefit of inhibiting SSAO in relapsing experimental autoimmune encephalomyelitis. J Neural Transm 2007;114:845-849.
56. Salter-Cid LM, Wang E, O'Rourke AM, Miller A, Gao H, Huang L, Garcia A, Linnik MD. Anti-inflammatory effects of inhibiting the amine oxidase activity of semicarbazide-sensitive amine oxidase. J Pharmacol Exp Ther 2005;315:553-562.
57. Wang EY, Gao H, Salter-Cid L, Zhang J, Huang L, Podar EM, Miller A, Zhao J, O'rourke A, Linnik MD. Design, synthesis, and biological evaluation of semicarbazide-sensitive amine oxidase (SSAO) inhibitors with anti-inflammatory activity. J Med Chem 2006;49:2166-2173.
58. O'Rourke AM, Wang EY, Miller A, Podar EM, Scheyhing K, Huang L, Kessler C, Gao H, Ton-Nu HT, Macdonald MT, Jones DS, Linnik MD. Anti-inflammatory effects of LJP 1586 [Z-3-fluoro-2-(4-methoxybenzyl)allylamine hydrochloride], an amine-based inhibitor of semicarbazide-sensitive amine oxidase activity. J Pharmacol Exp Ther 2008;324:867-875.
59. Martelius T, Salaspuro V, Salmi M, Krogerus L, H?ckerstedt K, Jalkanen S, Lautenschlager I. Blockade of vascular adhesion protein-1 inhibits lymphocyte infiltration in rat liver allograft rejection. Am J Pathol 2004;165:1993-2001.
60. Marttila-Ichihara F, Smith DJ, Stolen C, Yegutkin GG, Elima K, Mercier N, Kiviranta R, Pihlavisto M, Alaranta S, Pentik?inen U, Pentik?inen O, Fül?p F, Jalkanen S, Salmi M. Vascular amine oxidases are needed for leukocyte extravasation into inflamed joints in vivo. Arthritis Rheum 2006;54:2852-2862.
2. Boomsma F, de Kam PJ, Tjeerdsma G, van den Meiracker AH, van Veldhuisen DJ. Plasma semicarbazide-sensitive amine oxidase (SSAO) is an independent prognostic marker for mortality in chronic heart failure. Eur Heart J 2000;21:1859-1863.
3. Andres N, Lizcano JM, Rodriguez MJ, Romera M, Unzeta M, Mahy N. Tissue Activity and Cellular Localization of Human Semicarbazide-sensitive Amine Oxidase. J Histochem. Cytochem 2001;49:209-217.
4. Enrique-Tarancón G, Castan I, Morin N, Marti L, Abella A, Camps M, Casamitjana R, Palacín M, Testar X, Degerman E, CarpénéC, Zorzano A. Substrates of semicarbazide-sensitive amine oxidase co-operate with vanadate to stimulate tyrosine phosphorylation of insulin-receptor-substrate proteins, phosphoinositide 3-kinase activity and GLUT4 translocation in adipose cells. Biochem J 2000;350:171-180.
5. Enrique-Tarancón G, Marti L, Morin N, Lizcano JM, Unzeta M, Sevilla L, Camps M, Palacín M, Testar X, CarpénéC, Zorzano A. Role of semicarbazide-sensitive amine oxidase on glucose transport and GLUT4 recruitment to the cell surface in adipose cells. J Biol Chem 1998;273:8025-8032.
6. El Hadri K, Moldes M, Mercier N, Andreani M, Pairault J, Feve B. Semicarbazide-sensitive amine oxidase in vascular smooth muscle cells: differentiation-dependent expression and role in glucose uptake. Arterioscler Thromb Vasc Biol 2002;22:89-94.
7. Stolen CM, Yegutkin GG, Kurkij?rvi R, Bono P, Alitalo K, Jalkanen S. Origins of serum semicarbazide-sensitive amine oxidase. Circ Res 2004;95:50-57.
8. Lyles GA. Mammalian plasma and tissue-bound semicarbazide-sensitive amine oxidases: biochemical, pharmacological and toxicological aspects. Int J Biochem Cell Biol 1996;28:259-274.
9. Stolen CM, Madanat R, Marti L, Kari S, Yegutkin GG, Sariola H, Zorzano A, Jalkanen S. Semicarbazide-sensitive amine oxidase overexpression has dual consequences: insulin mimicry and diabetes-like complications. FASEB J 2004;18:702-704.
10. Bono P, Salmi M, Smith DJ, Jalkanen S. Cloning and characterization of mouse vascular adhesion protein-1 reveals a novel molecule with enzymatic activity. J Immunol 1998;160:5563-5571.
11. Smith DJ, Salmi M, Bono P, Hellman J, Leu T, Jalkanen S. Cloning of vascular adhesion protein 1 reveals a novel multifunctional adhesion molecule. J Exp Med 1998;188:17-27.
12. Salmi M, Jalkanen S. VAP-1: an adhesion and an enzyme. Trends Immunol 2001;22:211-216.
13. Tohka S, Laukkanen M, Jalkanen S, Salmi M. Vascular adhesion protein-1(VAP-1) functions as a molecular brake during granulocyte rolling and mediates recruitment in vivo. FASEB J 2001;15:373-382.
14. Salmi M, Yegutkin GG, Lehvonen R, Koskinen K, Salminen T, Jalkanen S. A cell surface amine oxidase directly controls lymphocyte migration. Immunity 2001;14:265-276.
15. Koskinen K, Vainio PJ, Smith DJ, Pihlavisto M, Yl?-Herttuala S, Jalkanen S, Salmi M. Granulocyte transmigration through the endothelium is regulated by the oxidase activity of vascular adhesion protein-1 (VAP-1). Blood 2004;103:3388-3395.
16. Jalkanen S, Karikoski M, Mercier N, Koskinen K, Henttinen T, Elima K, Salmivirta K, Salmi M. The oxidase activity of vascular adhesion protein-1 (VAP-1) induces endothelial E- and P-selectins and leukocyte binding. Blood 2007;110:1864-1870.
17. O’Sullivan J, Unzeta M, Healy J, O’Sullivan MI, Davey G, Tipton KF. Semicarbazide-sensitive amine oxidases: enzymes with quite a lot to do. Neurotoxicology 2004;25:303-315.
18. Deng Y, Boomsma F, Yu PH. Deamination of methylamine and aminoacetone increases aldehydes and oxidative stress in rats. Life Sci 1998;63:2049-2058.
19. Lichszteld K, Kruk I. Singlet molecular oxygen in formaldehyde oxidation. Z Phys Chem 1977;108:167-172.
20. Ucar G, Topaloglu E, Burak Kandilci H, Gumusel B. Elevated semicarbazide-sensitive amine oxidase (SSAO) activity in lung with ischemia-reperfusion injury: protective effect of ischemic preconditioning plus SSAO inhibition. Life Sci 2005;78:421-427.
21. Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 2003;285:579-588.
22. Kin H, Zhao ZQ, Sun HY, Wang NP, Corvera JS, Halkos ME, Kerendi F, Guyton RA, Vinten-Johansen J. Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion. Cardiovasc Res 2004;62:74-85.
23. Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L'Huillier I, Aupetit JF, Bonnefoy E, Finet G, André-Fou?t X, Ovize M. Postconditioning the human heart. Circulation2005;112:2143-2148.
24. Hausenloy DJ, Yellon DM. Preconditioning and postconditioning: united at reperfusion. Pharmacol Ther 2007;116:173-191.
25. Zhao TC, Cheng G, Zhang LX, Tseng YT, Padbury JF. Inhibition of histone deacetylases triggers pharmacologic preconditioning effects against myocardial ischemic injury. Cardiovasc Res 2007;76:473-481.
26. Kloner RA, Rezkalla SH. Preconditioning, postconditioning and their application to clinical cardiology. Cardiovasc Res 2006;70:297-307.
27. Roberts AJ, Cipriano PR, Alonso DR, Jacbostein JG, Combes JR, Gay WA Jr. Evaluation of methods for the quantification of experimental myocardial infarction. Circulation 1978;57:35-41.
28. Li H, Luo WH, Lin JJ, Lin Z, Zhang Y. Assay of plasma semicarbazide-sensitive amine oxidase and determination of its endogenous substrate methylamine by liquid chromatography. J Chromatogr B 2004;810:277-282.
29. Paradies G, Petrosillo G, Pistolese M, Venosa ND, Serena D, Ruggiero FM. Lipid peroxidation and alterations to oxidative metabolism in mitochondria isolated from rat heart subjected to ischemia and reperfusion. Free Radical Biol Med 1999;27:42-50.
30. Ambrosio G, Flaherty JT, Duilio C, Tritto I, Santoro G, Elia PP, Condorelli M, Chiariello M. Oxygen radicals generated at reflow induce peroxidation of membrane lipids in reperfused hearts. J Clin Invest 1991;87:2056-2066.
31. Nicholls SJ, Hazen SL. Myeloperoxidase and cardiovascular disease. Arterioscler Thromb Vasc Biol 2005;25:1102-1111.
32. Brennan ML, Penn MS, Van Lente F, Nambi V, Shishehbor MH, Aviles RJ, Goormastic M, Pepoy ML, McErlean ES, Topol EJ, Nissen SE, Hazen SL. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med 2003;349:1595-1604.
33. Kinemuchi H, Sugimoto H, Obata T, Satoh N, Ueda S. Selective inhibitors of membrane-bound semicarbazide-sensitive amine oxidase (SSAO) activity in mammalian tissues. NeuroToxicology 2004;25:325-335.
34. Conklin DJ, Cowley HR, Wiechmann RJ, Johnson GH, Trent MB, Boor PJ. Vasoactive effects of methylamine in isolated human blood vessels: role of semicarbazide-sensitive amine oxidase, formaldehyde, and hydrogen peroxide. Am J Physiol Heart Circ Physiol 2004;286:667-673.
35. Jaakkola K, Jalkanen S, Kaunism?ki K, V?nttinen E, Saukko P, Alanen K, Kallajoki M, Voipio-Pulkki LM, Salmi M. Vascular adhesion protein-1, intercellular adhesion molecule-1and P-selectin mediate leukocyte binding to ischemic heart in humans. J AM Coll Cardiol 2000;36:122-129.
36. Xu HL, Salter-Cid L, Linnik MD, Wang EY, Paisansathan C, Pelligrino DA. Vascular adhesion protein-1 plays an important role in postischemic inflammation and neuropathology in diabetic, estrogen-treated ovariectomized female rats subjected to transient forebrain ischemia. J Pharmacol Exp Ther 2006;317:19-29.
37. Kiss J, Jalkanen S, Fül?p F, Savunen T, Salmi M. Ischemia-reperfusion injury is attenuated in VAP-1-deficient mice and by VAP-1 inhibitors. Eur J Immunol 2008;38:3041-3049.
38. Tsutsumi YM, Yokoyama T, Horikama Y, Roth DM, Patel HH. Reactive oxygen species trigger ischemic and pharmacological postconditioning: in vivo and in vitro characterization. Life Sci 2007;81:1223-1227.
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