Role of CD73 in cardiac injury in rats with chronic intermittent hypoxia combined with high fat diet_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

ZHANG Xiuli ¹ ,  YU Qing ² , WANG Xiaoya ² , LI Juanzhi ¹ , ZHAO Hong ¹

1. The First Clinical Medical School of Lanzhou University, Lanzhou, Gansu 730000, P. R. China;
2. Department of Respiratory Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P. R. China;

Corresponding author：

YU Qing, Email: yuq701@163.com

Keywords：

Obstructive sleep apnea hypopnea syndrome; Chronic intermittent hypoxia; High fat diet; CD73; Myocardial injury

DOI：

10.7507/1671-6205.201702031

Video：

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ObjectiveTo investigate the expression and significance of CD73 in rats with intermittent hypoxia and high fat diet.MethodsThe rat model of chronic intermittent hypoxia combined with high fat diet was established. Twenty-four healthy male Wistar rats in the SPF level were randomly divided into 4 group, with 6 rats in each group, namely group A (normoxia and normal diet), group B (normoxia and high fat diet), group C (intermittent hypoxia and normal diet)and group D (intermittent hypoxia and high-fat diet). After 6 weeks of experiment, the serum lipid levels, myocardial morphological changes under microscope, the expression level of CD73 protein detected byimmunohistochemistry and Western blot in myocardial cells in rats were compared among these groups.ResultsThe serum lipid levels were significantly different among these groups (P<0.05). HE results showed that the myocardial cells of group A had no obvious abnormalities; disorganized visible myocardial fibers with focal necrosis in groups B and C; myocardial cell injury was most obvious in group D, in which visible muscle fibers arranged in disorder, and grain was not clear, part of the muscle fibers were dissolved predominantly. Compared with group A, CD73 protein expression levels in myocardial cells in groups B, C, and D were significantly elevated (P<0.01). Furthermore, CD73 protein expression level in myocardial cells in group D was significantly higher than those in groups B and C (P<0.01). Western blot showed consistent results as immunohistochemistry: compared with group A, CD73 protein expression levels in groups B, C, and D were significantly elevated (P<0.05), and CD73 protein expression level in myocardial cells in group D was significantly higher than those in groups B and C (P<0.01).ConclusionChronic intermittent hypoxia and high fat diet can cause myocardial cell damage and upregulate CD73 expression in the cardiomyocytes.

Citation： ZHANG Xiuli, YU Qing, WANG Xiaoya, LI Juanzhi, ZHAO Hong. Role of CD73 in cardiac injury in rats with chronic intermittent hypoxia combined with high fat diet. Chinese Journal of Respiratory and Critical Care Medicine, 2017, 16(5): 478-483. doi: 10.7507/1671-6205.201702031 Copy

1.	Van Eyck A, Van Hoorenbeeck K, De Winter BY, et al. Sleep-disordered breathing, systemic adipokine secretion, and metabolic dysregulation in overweight and obese children and adolescents. Sleep Med, 2017, 30(期): 52-56.
2.	Wang H, Tian JL, Feng SZ, et al. The organ specificity in pathological damage of chronic intermittent hypoxia: an experimental study on rat with high-fat diet. Sleep Breath, 2013, 17(3): 957-965.
3.	苏奕亮, 李惠萍, 刘锦铭, 等. 阻塞性睡眠呼吸暂停低通气综合征夜间低氧血症对 ACS 患者颈动脉斑块的影响. 中华医学会呼吸病学年会——2013 (第十四次全国呼吸病学学术会议论文集[C]. 中国辽宁大连, F, 2013.
4.	Antonioli L, Pacher P, Vizi ES, et al. CD39 and CD73 in immunity and inflammation. Trends in Molecular Medicine, 2013, 19(6): 355.
5.	Alam MS, Kuo JL, Ernst PB, et al. Ecto-5'-nucleotidase (CD73) regulates host inflammatory responses and exacerbates murine salmonellosis. Sci Rep, 2014, 4: 4486.
6.	Zhu J, Zeng Y, Li W, et al. CD73/NT5E is a target of miR-30a-5p and plays an important role in the pathogenesis of non-small cell lung cancer. Mol Cancer, 2017, 16(1): 34.
7.	Pettengill M, Robson S, Tresenriter M, et al. Soluble ecto-5'-nucleotidase (5'-NT), alkaline phosphatase, and adenosine deaminase (ADA1) activities in neonatal blood favor elevated extracellular adenosine. J Biol Chem, 2013, 288(38): 27315-27326.
8.	Kaniewska E, Sielicka A, Sarathchandra P, et al. Immunohistochemical and functional analysis of ectonucleoside triphosphate diphosphohydrolase 1 (CD39) and ecto-5'-nucleotidase (CD73) in pig aortic valves. Nucleosides Nucleotides Nucleic Acids, 2014, 33(4-6): 305-312.
9.	Wheeler DG, Joseph ME, Mahamud SD, et al. Transgenic swine: expression of human CD39 protects against myocardial injury. J Mol Cell Cardiol, 2012, 52(5): 958-961.
10.	李兰凤. 还原型谷胱甘肽对间歇低氧大鼠下丘脑—垂体—肾上腺轴超微结构及功能的干预机制研究 [D]. 兰州大学, 2015.
11.	Wang X, Yu Q, Yue H, et al. Effect of Intermittent Hypoxia and Rimonabant on Glucose Metabolism in Rats: Involvement of Expression of GLUT4 in Skeletal Muscle. Medical Science Monitor International Medical Journal of Experimental & Clinical Research, 2015, 21: 3252-3260.
12.	冯靖, 陈宝元, 郭美南, 等. 间歇低氧气体环境模型的建立.天津医科大学学报, 2006, 12(4): 509-512.0.
13.	Xia Y, Fu Y, Wang Y, et al. Prevalence and Predictors of Atherogenic Serum Lipoprotein Dyslipidemia in Women with Obstructive Sleep Apnea. Sci Rep, 2017, 7: 41687.
14.	Savransky V, Nanayakkara A, Li J, et al. Chronic intermittent hypoxia induces atherosclerosis. Am J Respir Crit Care Med, 2007, 175(12): 1290-1297.
15.	Savransky V, Bevans S, Nanayakkara A, et al. Chronic intermittent hypoxia causes hepatitis in a mouse model of diet-induced fatty liver. Am J Physiol Gastrointest Liver Physiol, 2007, 293(4): G871-877.
16.	姚爱华. 阻塞性睡眠呼吸暂停低通气综合征与心血管疾病的关系. 医疗装备, 2017, (01): 141-142.0.
17.	Maruyama K, Morishita E, Sekiya A, et al. Plasma levels of platelet-derived microparticles in patients with obstructive sleep apnea syndrome. J Atheroscler Thromb, 2012, 19(1): 98-104.
18.	韦华清, 兰枝东, 韦岑, et al. 阻塞性睡眠呼吸暂停低通气综合征对心脏的影响. 临床心血管病杂志, 2013, (01): 57-59.0.
19.	曾双, 汪小亚, 崔芬芬, 等. 阻塞性睡眠呼吸暂停低通气综合征与胰岛素抵抗相关性的研究进展. 中国呼吸与危重监护杂志, 2016, (02): 210-212.0.
20.	Catala R, Villoro R, Merino M, et al. Cost-effectiveness of Continuous Positive Airway Pressure Treatment in Moderate-Severe Obstructive Sleep Apnea Syndrome. Arch Bronconeumol, 2016, 52(9): 461-469.
21.	Chang YL, Tseng TM, Chen PY, et al. Using temperature-time integration as a critical parameter in using monopolar radiofrequency ablations. Eur Arch Otorhinolaryngol, 2014, 271(7): 1973-1979.
22.	兰国斌, 蔡少雄, 王智泉, 等. 阻塞性睡眠呼吸暂停综合征和高血压的线粒体功能临床研究分析; 中国转化医学和整合医学研讨会(广州站)论文集[C]. 中国广东广州, F, 2015.
23.	崔芬芬. 间歇性低氧对大鼠心肌超微结构和心肌糖代谢的影响及利莫那班的干预作用 [D]. 兰州大学, 2016.
24.	Covarrubias R, Chepurko E, Reynolds A, et al. Role of the CD39/CD73 Purinergic Pathway in Modulating Arterial Thrombosis in Mice. Arterioscler Thromb Vasc Biol, 2016, 36(9): 1809-1820.
25.	Wolff G, Truse R, Decking U. Extracellular Adenosine Formation by Ecto-5'-Nucleotidase (CD73) Is No Essential Trigger for Early Phase Ischemic Preconditioning. PLoS One, 2015, 10(8): e0135086.
26.	Ochaion A, Bar-Yehuda S, Cohen S, et al. The A3 adenosine receptor agonist CF502 inhibits the PI3K, PKB/Akt and NF-kappaB signaling pathway in synoviocytes from rheumatoid arthritis patients and in adjuvant-induced arthritis rats. Biochem Pharmacol, 2008, 76(4): 482-494.
27.	Terashima Y, Sato T, Yano T, et al. Roles of phospho-GSK-3beta in myocardial protection afforded by activation of the mitochondrial K ATP channel. J Mol Cell Cardiol, 2010, 49(5): 762-770.
28.	Cai M, Huttinger ZM, He H, et al. Transgenic over expression of ectonucleotide triphosphate diphosphohydrolase-1 protects against murine myocardial ischemic injury. J Mol Cell Cardiol, 2011, 51(6): 927-935.
29.	Jesurum JT, Fuller CJ, Murinova N, et al. Aspirin's effect on platelet inhibition in migraineurs. Headache, 2012, 52(8): 1207-1218.
30.	Motoda C, Ueda H, Hayashi Y, et al. Impact of platelet reactivity to adenosine diphosphate before implantation of drug-eluting stents on subsequent adverse cardiac events in patients with stable angina. Circ J, 2012, 76(3): 641-649.
31.	杨佳音, 简蓉蓉, 许雅丽, 等. CD73 对动脉粥样硬化中血管平滑肌细胞的作用. 复旦学报(医学版), 2015, (03): 300-306.0.
32.	Zukowska P, Kutryb-Zajac B, Jasztal A, et al. Deletion of CD73 in mice leads to Aortic Valve Dysfunction. Biochim Biophys Acta, 2017, :.
33.	Li X, Zhou T, Zhi X, et al. Effect of hypoxia/reoxygenation on CD73 (ecto-5'-nucleotidase) in mouse microvessel endothelial cell lines. Microvasc Res, 2006, 72(1-2): 48-53.
34.	Jalkanen J, Yegutkin GG, Hollmen M, et al. Aberrant circulating levels of purinergic signaling markers are associated with several key aspects of peripheral atherosclerosis and thrombosis. Circ Res, 2015, 116(7): 1206-1215.

1. Van Eyck A, Van Hoorenbeeck K, De Winter BY, et al. Sleep-disordered breathing, systemic adipokine secretion, and metabolic dysregulation in overweight and obese children and adolescents. Sleep Med, 2017, 30(期): 52-56.
2. Wang H, Tian JL, Feng SZ, et al. The organ specificity in pathological damage of chronic intermittent hypoxia: an experimental study on rat with high-fat diet. Sleep Breath, 2013, 17(3): 957-965.
3. 苏奕亮, 李惠萍, 刘锦铭, 等. 阻塞性睡眠呼吸暂停低通气综合征夜间低氧血症对 ACS 患者颈动脉斑块的影响. 中华医学会呼吸病学年会——2013 (第十四次全国呼吸病学学术会议论文集[C]. 中国辽宁大连, F, 2013.
4. Antonioli L, Pacher P, Vizi ES, et al. CD39 and CD73 in immunity and inflammation. Trends in Molecular Medicine, 2013, 19(6): 355.
5. Alam MS, Kuo JL, Ernst PB, et al. Ecto-5'-nucleotidase (CD73) regulates host inflammatory responses and exacerbates murine salmonellosis. Sci Rep, 2014, 4: 4486.
6. Zhu J, Zeng Y, Li W, et al. CD73/NT5E is a target of miR-30a-5p and plays an important role in the pathogenesis of non-small cell lung cancer. Mol Cancer, 2017, 16(1): 34.
7. Pettengill M, Robson S, Tresenriter M, et al. Soluble ecto-5'-nucleotidase (5'-NT), alkaline phosphatase, and adenosine deaminase (ADA1) activities in neonatal blood favor elevated extracellular adenosine. J Biol Chem, 2013, 288(38): 27315-27326.
8. Kaniewska E, Sielicka A, Sarathchandra P, et al. Immunohistochemical and functional analysis of ectonucleoside triphosphate diphosphohydrolase 1 (CD39) and ecto-5'-nucleotidase (CD73) in pig aortic valves. Nucleosides Nucleotides Nucleic Acids, 2014, 33(4-6): 305-312.
9. Wheeler DG, Joseph ME, Mahamud SD, et al. Transgenic swine: expression of human CD39 protects against myocardial injury. J Mol Cell Cardiol, 2012, 52(5): 958-961.
10. 李兰凤. 还原型谷胱甘肽对间歇低氧大鼠下丘脑—垂体—肾上腺轴超微结构及功能的干预机制研究 [D]. 兰州大学, 2015.
11. Wang X, Yu Q, Yue H, et al. Effect of Intermittent Hypoxia and Rimonabant on Glucose Metabolism in Rats: Involvement of Expression of GLUT4 in Skeletal Muscle. Medical Science Monitor International Medical Journal of Experimental & Clinical Research, 2015, 21: 3252-3260.
12. 冯靖, 陈宝元, 郭美南, 等. 间歇低氧气体环境模型的建立.天津医科大学学报, 2006, 12(4): 509-512.0.
13. Xia Y, Fu Y, Wang Y, et al. Prevalence and Predictors of Atherogenic Serum Lipoprotein Dyslipidemia in Women with Obstructive Sleep Apnea. Sci Rep, 2017, 7: 41687.
14. Savransky V, Nanayakkara A, Li J, et al. Chronic intermittent hypoxia induces atherosclerosis. Am J Respir Crit Care Med, 2007, 175(12): 1290-1297.
15. Savransky V, Bevans S, Nanayakkara A, et al. Chronic intermittent hypoxia causes hepatitis in a mouse model of diet-induced fatty liver. Am J Physiol Gastrointest Liver Physiol, 2007, 293(4): G871-877.
16. 姚爱华. 阻塞性睡眠呼吸暂停低通气综合征与心血管疾病的关系. 医疗装备, 2017, (01): 141-142.0.
17. Maruyama K, Morishita E, Sekiya A, et al. Plasma levels of platelet-derived microparticles in patients with obstructive sleep apnea syndrome. J Atheroscler Thromb, 2012, 19(1): 98-104.
18. 韦华清, 兰枝东, 韦岑, et al. 阻塞性睡眠呼吸暂停低通气综合征对心脏的影响. 临床心血管病杂志, 2013, (01): 57-59.0.
19. 曾双, 汪小亚, 崔芬芬, 等. 阻塞性睡眠呼吸暂停低通气综合征与胰岛素抵抗相关性的研究进展. 中国呼吸与危重监护杂志, 2016, (02): 210-212.0.
20. Catala R, Villoro R, Merino M, et al. Cost-effectiveness of Continuous Positive Airway Pressure Treatment in Moderate-Severe Obstructive Sleep Apnea Syndrome. Arch Bronconeumol, 2016, 52(9): 461-469.
21. Chang YL, Tseng TM, Chen PY, et al. Using temperature-time integration as a critical parameter in using monopolar radiofrequency ablations. Eur Arch Otorhinolaryngol, 2014, 271(7): 1973-1979.
22. 兰国斌, 蔡少雄, 王智泉, 等. 阻塞性睡眠呼吸暂停综合征和高血压的线粒体功能临床研究分析; 中国转化医学和整合医学研讨会(广州站)论文集[C]. 中国广东广州, F, 2015.
23. 崔芬芬. 间歇性低氧对大鼠心肌超微结构和心肌糖代谢的影响及利莫那班的干预作用 [D]. 兰州大学, 2016.
24. Covarrubias R, Chepurko E, Reynolds A, et al. Role of the CD39/CD73 Purinergic Pathway in Modulating Arterial Thrombosis in Mice. Arterioscler Thromb Vasc Biol, 2016, 36(9): 1809-1820.
25. Wolff G, Truse R, Decking U. Extracellular Adenosine Formation by Ecto-5'-Nucleotidase (CD73) Is No Essential Trigger for Early Phase Ischemic Preconditioning. PLoS One, 2015, 10(8): e0135086.
26. Ochaion A, Bar-Yehuda S, Cohen S, et al. The A3 adenosine receptor agonist CF502 inhibits the PI3K, PKB/Akt and NF-kappaB signaling pathway in synoviocytes from rheumatoid arthritis patients and in adjuvant-induced arthritis rats. Biochem Pharmacol, 2008, 76(4): 482-494.
27. Terashima Y, Sato T, Yano T, et al. Roles of phospho-GSK-3beta in myocardial protection afforded by activation of the mitochondrial K ATP channel. J Mol Cell Cardiol, 2010, 49(5): 762-770.
28. Cai M, Huttinger ZM, He H, et al. Transgenic over expression of ectonucleotide triphosphate diphosphohydrolase-1 protects against murine myocardial ischemic injury. J Mol Cell Cardiol, 2011, 51(6): 927-935.
29. Jesurum JT, Fuller CJ, Murinova N, et al. Aspirin's effect on platelet inhibition in migraineurs. Headache, 2012, 52(8): 1207-1218.
30. Motoda C, Ueda H, Hayashi Y, et al. Impact of platelet reactivity to adenosine diphosphate before implantation of drug-eluting stents on subsequent adverse cardiac events in patients with stable angina. Circ J, 2012, 76(3): 641-649.
31. 杨佳音, 简蓉蓉, 许雅丽, 等. CD73 对动脉粥样硬化中血管平滑肌细胞的作用. 复旦学报(医学版), 2015, (03): 300-306.0.
32. Zukowska P, Kutryb-Zajac B, Jasztal A, et al. Deletion of CD73 in mice leads to Aortic Valve Dysfunction. Biochim Biophys Acta, 2017, :.
33. Li X, Zhou T, Zhi X, et al. Effect of hypoxia/reoxygenation on CD73 (ecto-5'-nucleotidase) in mouse microvessel endothelial cell lines. Microvasc Res, 2006, 72(1-2): 48-53.
34. Jalkanen J, Yegutkin GG, Hollmen M, et al. Aberrant circulating levels of purinergic signaling markers are associated with several key aspects of peripheral atherosclerosis and thrombosis. Circ Res, 2015, 116(7): 1206-1215.

Chinese Journal of Respiratory and Critical Care Medicine

Role of CD73 in cardiac injury in rats with chronic intermittent hypoxia combined with high fat diet

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