慢性炎症与血管疾病研究室

　　Postdoctoral Scholar, Department of Micro./Immunology and Department of Physiology, Loyola University of Chicago Stritch School of Medicine, Maywood, Illinois, USA

　　工作经历

　　Professional Experience

　　1980.1-1986.1 北京医科大学病理生理学教研室讲师

　　Teaching and Research Associate, Department of Pathophysiology, Beijing Medical University, Beijing, P. R. China

　　1988.3-2000.2 北京大学第三医院血管医学研究所研究员、副所长

　　Researcher and Vice President of Institute of Vascular Medicine, Peking University Third Hospital, Beijing, P. R. China

　　2000.3-至今北京大学医学部生理学与病理生理学系教授, 主任

　　Professor and Chairman of Department of Physiology and Pathophysiology, Health Science Center of Peking University, Beijing, P. R. China

　　2006.9-2015.6 北京大学医学部副主任

　　Vice President of Peking University, Health Science Center, Beijing, P. R. China

　　研究室成员：

　　姜长涛特聘研究员

　　冯娟助理研究员

　　郭玲主管技师

　　刘博主管技师

　　研究室概述：

　　研究方向1：慢性炎症与动脉粥样硬化和代谢性血管病变

　　动脉粥样硬化是当今世界上严重威胁人类健康的最常见的疾病，每年全世界约有1200万人死于动脉粥样硬化并发症。本室近十年来从寻找心血管疾病发病新的危险因子出发，曾在国际上最先报道了引起动脉粥样硬化发病新的独立危险因子高同型半胱氨酸血症（Hyperhomocysteinemia, HHcy）通过激活多种致炎的免疫反应，加速动脉粥样硬化和胰岛素抵抗伴发的血管病变的发生。目前就其分子发病机制正进行深入的研究。

　　研究方向2：内源性血管活性物质对心血管的保护作用及其机制

　　自稳态的维持是生命存在的基本条件，心血管系统的稳态失衡是各种血管损伤性疾病的共同发病基础。神经、内分泌和心血管旁/自分泌系统产生多种生物活性物质，对心血管结构和功能的稳态进行精密的调节。本室十几年来从寻找内源性拮抗心血管损伤的活性多肽及其网络调控出发，在国际上首先报道了降钙素基因相关肽家族的几种活性肽的炎症上调机制和心血管保护作用机制。目前正针对其内源性网络调控的保护机制进行深入研究。

　　研究方向3：细胞外基质及基质水解酶在血管重塑中的作用

　　基质的合成和降解参与了动脉粥样硬化斑块形成、斑块破裂以及血管再狭窄的发生和发展。本室研究集中在金属蛋白酶的新家族ADAMTS在上述心血管疾病中的作用。首先在国际上报道ADAMTS-7介导了血管损伤后再狭窄的发病过程。目前就其分子机制正进行深入研究。此外，还致力于研究细胞外基质蛋白对于维持血管细胞正常表型及对血管钙化形成的影响。

　　Research Description:

　　1. Chronic inflammation, atherosclerosis and metabolic vascular disorders. Atherosclerosis is the most common and fetal disease, 12 million people died of atherosclerosis and its complications each year. In recent 10 years, our lab focuses on seeking new risk factors of cardiovascular diseases. We have reported firstly in the world that hyperhomocysteinemia, the independent risk factor of atherosclerosis, accelerates the pathogenesis of atherosclerosis and insulin resistance concomitant vascular disorders. We are now approaching the related molecular mechanism.

　　2. Protection effect of endogenous vasculoactive substances on cardiovascular system and the mechanism. Homeostasis is the essential for life, disbalance of cardiovascular homeostasis is the common pathogenesis of vascular disorders. Many bioactive substances are synthesized by neural, endocrinal and cardiovascular para/autocrine system and regulate the homeostasis of cardiovascular structure and function precisely. For more than 10 years, our lab focuses on seeking the endogenous vasculoactive peptides antagonizing cardiovascular injury and the regulating network. We have reported firstly in the world that the CGRP superfamily could be upregulated by inflammation and protect cardiovascular system. We are now approaching the protecting mechanism of its endogenous network regulation.

　　3. Extracellular proteases play a key role during atherosclerosis and restenosis. The relevance of ADAMTS family members in cardiovascular disease is just now being addressed, but the precise effects and underlying mechanisms are poorly understood. Our primary interest is focused on the effect of ADAMTS-7 on the evolution and progression of atherosclerosis, as well on plaque rupture. Our

　　studies apply a combination of biochemistry, cell biology, and genetics to elucidate fundamental mechanisms that governing ADAMTS-7 activation and signaling, and to illuminate their pathophysiological impact during atherogenesis. Our studies demonstrate that ADAMTS-7 is transcriptional regulated by proatherosclerotic factors including inflammatory cytokines. ADAMTS-7 is required for VSMCs migration and intima thickening. Future studies will further explore potential possibility of ADAMTS-7 as a novel target for atherosclerosis and serum ADAMTS-7 level as biomarker for atherosclerosis progression.

　　Selected Publications (2004-Present):

　　1. Dai XY, Cai Y, Sun W, Ding Y, Wang W, Kong W, Tang C, Zhu Y, Xu MJ*, Wang X. Intermedin inhibits macrophage foam-cell formation via tristetraprolin-mediated decay of CD36 mRNA.Cardiovasc Res. 2014 Feb 1;101(2):297-305.

　　2. Ma K, Lv S, Liu B, Liu Z, Luo Y, Kong W, Xu Q, Feng J*, Wang X*. CTLA4-IgG Ameliorates Homocysteine-accelerated Atherosclerosis by Inhibiting T-cell Overactivation in ApoE-/- Mice.Cardiovasc Res.2013;97:349-359.

　　3. Dai XY, Zhao MM, Cai Y, Guan QC, Zhao Y, Guan Y, Kong W, Zhu WG, Xu MJ*, Wang X. Phosphate-induced autophagy counteracts vascular calcification by reducing matrix vesicle release. Kidney Int.2013;83:1042-1051.

　　4. Liu ZY, Luo HZ, Zhang L, Huang YQ, Liu B, Ma KY, Feng J, Xie JS, Zheng JG, Hu J, Zhan SY, Zhu Y, Xu QB, Kong Wei *,Xian Wang*. Hyperhomocysteinemia Exaggerates Adventitial Inflammation and Angiotensin II？Induced Abdominal Aortic Aneurysm in Mice. Circ Res. 2012;111:1261-73.

　　5. Zhao GX , Xu MJ, Zhao MM, Dai XY, Kong W, Gerald M. Wilson, Guan YF, Wang CY*, Xian Wang*. Activation of nuclear factor-kappa B accelerates vascular calcification by inhibiting progressive ankylosis protein homolog expression. Kidney Int，2012;82:34-44.

　　6. Zhao M, Xu M, Cai Y, Zhao G, Guan Y, Kong W, Tang C, Wang X*. Mitochondrial reactive oxygen species promote p65 nuclear translocation mediating high-phosphate-induced vascular calcification in vitro and in vivo. Kidney Int. 2011, 79:1071-1079.

　　7. Wang L, Zheng JG, Bai X, Liu B, Liu CJ, Xu Q, Zhu Y, Wang N, Kong W and Wang X. ADAMTS-7 Mediates Vascular Smooth Muscle Cell Migration and Neointima Formation in Balloon-injured Rat Arteries. Circ. Res. 2009;104:688-698.

　　8. Feng, J., Z. Zhang, W. Kong, B. Liu, Q. Xu, X. Wang. Regulatory T cells ameliorate hyperhomocysteinemia-accelerated atherosclerosis in ApoE-/- mice. Cardiovas Res. 2009, 84:155-163.

　　9. Qu, A., C. Jiang, M. Xu, Y. Zhang, Y. Zhu, Q. Xu, C. Zhang, X. Wang. PGC-1α attenuates neointimal formation via inhibition of vascular smooth muscle cell migration in the injured rat carotid artery. Am J Physiol Cell Physiol, 2009, 297:C645-653.

　　10. Wang，G., Z. Zhang, J. Yu, F. Zhang, L. He, J. Wei, J. Mao, X. Wang. Antidiabetic rosiglitazone reduces soluble intercellular adhesion molecules-1 levels in type 2 diabetic patients with coronary artery disease. PPAR Res, 2008, Epub, Dec 18.

　　11. Dai, J., X. Wang, J. Feng, W. Kong, Q. Xu, X. Shen, X. Wang. Regulatory role of thioredoxin in homocysteine-induced monocyte chemoattractant protein-1 secretion in human monocytes. FEBS Lett, 2008, 582:3893-3898.

　　12. Li，Y, C. Jiang, G. Xu, N. Wang, Y. Zhu, C. Tang, X. Wang. Homocysteine upregulates resistin production from adipocytes in vivo and in vitro. Diabetes 2008，57:817-827.

　　13. Jia, L., W. Wang, W. Zhen, M. Xu, X. Shen, Y. Zhu, X. Wang. Novel anti-oxidative role of calreticulin in protecting A549 human type II alveolar epithelial cells against hypoxic injury. Am J Physiol Cell Physiol, 2008, 294:C47-55.

　　14. Dai, J., X. Wang. Immunoregulatory effects of homocysteine on cardiovascular diseases. 生理学报，2007，59: 5: 585-592 (特邀综述).

　　15. Jie Yu*., Nan Jin*., Guang Wang, Fuchun Zhang, Jieming Mao, Xian Wang. PPAR-γ agonist improved arterial stiffness in type 2 diabetes patients with coronary artery disease. Metabolism, 2007，56：1396-1401

　　16. Li, W., S. Zheng, C. Tang, Y. Zhu, X. Wang. JNK-AP-1 pathway involved in interleukin-1b-induced calcitonin gene-related peptide secretion in human type II alveolar epithelial cells. Peptides 2007, 28:1252-1259.

　　17. Chang, L*., Z. Zhang*, W. Li, J. Dai, Y. Guan, X. Wang. Liver-X-receptor activator prevents the homocysteine-induced production of IgG antibody from murine B lymphocytes via ROS-NF-kB pathway. BBRC, 2007，357：772-8.

　　18. Yi Quan Y., J. Du, X. Wang. High Glucose Stimulates GRO Secretion from Rat Microglia via ROS, PKC and NF-кB pathways. J Neurosci Res, 2007，85：3150-59.

　　19. He R., A. Qu, J. Mao, X. Wang*, W. Sun. Synergistic proliferation induced by insulin and glycated serum albumin in rat vascular smooth muscle cells. Acta Physiol Sin 2007，59：1-7.

　　20. Chen, M., W. Li, N. Wang, Y. Zhu* and X. Wang*. ROS and NF-kB but not LXR mediate IL-1b signaling for the downregulation of ATP-binding cassette transporter A1. Am J Physiol Cell Physiol. 2007，292:C1493-C1501.

　　21. Li, W., T. Wang, X. Wang*. Calcitonin gene-related peptide inhibits interleukin1-b-induced interleukin-8 secretion in human type II alveolar epithelial cell. Acta Pharmocol Sin, 2006, 27: 1340-1345.

　　22. Li, W., T. Wang, C. Ma, T. Xiong, Y. Zhu, X. Wang*. Calcitonin gene-related peptide inhibits interleukin1-b-induced endogenous monocyte chemoattractant protein-1 secretion in human type II alveolar epithelial cell. Am J Physiol Cell Physiol. 2006, 291: C456-65.

　　23. Dai, J., W. Li, L. Chang, Z. Zhang, C. Tang, N. Wang, Y. Zhu, X. Wang*. Role of redox factor-1 in hyperhomocysteinemia accelerated atherosclerosis. Free Radical Bio Med, 2006, 41:1566-1577.

　　24. Jiang, H., X. Wang, L. Fang, C. Tang, Y. Zhu, X. Wang*. Upregulation of aldose reductase by homocysteine in type II alveolar epithelial cells. BBRC, 2005, 337:1084-1091

　　25. Sun, W., G. Wang，Z. Zhang, X. Zeng, X. Wang*.. Chemokine RANTES is upregulated in monocytes from patients with hyperhomocysteinemia. Acta Physiologica Sin, 2005, 26:1317-1321.

　　26. Zhu, Y.H., T. Ma, X. Wang*. Gene transfer of heat-shock protein 20 protects against ischemia/reperfusion injury in rat heart. Acta Pharmocol Sin, 2005, 1193-1200

　　27. Zhu, Y.H., X. Wang*. Overexpression of heart-shock protein 20 in rat heart myogenic cell confers protection against stimulated ischemia/reperfusion injury. Acta Pharmocol Sin, 2005, 26:1076-80

　　28. Qin, X., Y. Wan, X. Wang*. CCL2 and CXCL1 trigger calcitonin gene-related peptide release by exciting primary nociceptive neurons. J Neurosci Res 2005; 82:51-62.

　　29. Xie, L., L. Chang, Y. Guan，X. Wang*. C-Reactive Protein augments interleukin-8 production in human blood monocytes. J Cardiovas Pharmocal，2005, 46:690-696.

　　30. Wang, W., L. Jia, T. Wang, W. Sun, S. Wu, X. Wang*. Endogenous calcitonine gene-related peptide protects human alveolar cells through protein kinase Ce and heat shock protein. J Biol Chem, 2005, 280:20325-20330

　　31. Zeng, X., Y. Guan, D.G. Remick, X. Wang*. Signal pathways underlying homocysteine-induced production of MCP-1 and IL-8 in cultured human whole blood. Acta Pharmocol Sin, 2005, 26:85-91.

　　32.Wang, G., J. Mao, X. Yang, X. Wang*. Folic acid reverses hyper-responsiveness of LPS-induced chemokine secretion from monocytes in patients with hyperhomocysteinemia. Atherosclerosis, 2005，179：395-402

　　33. Li, W, L. Hou, Z. Hua, X. Wang*. Interleukin-1β induces β-calcitonin gene-related peptide secretion in human type II alveolar epithelial cells. FASEB J, 2004;18:1603-1605, fj.04-1737

　　34. Wang, G., J. Wei, Y. Guan, J. Mao, X. Wang*. Peroxisome proliferators-activated receptor-γ agonist rosiglitazone reduces clinical inflammatory responses in type 2 diabetes with coronary artery disease after coronary angioplasty. Metabolism, 2005,54:590-597

　　35. Zeng, X., D. G. Remick, X. Wang*. Homocysteine induces the secretion of monocyte chemoattractant protein-1 and interleukin–8 in cultured human whole blood. Acta Pharmocol Sinica, 2004, 25:1419-1425

　　36. Wang, W., W. Sun，X. Wang*. Intramuscular gene transfer of CGRP inhibits neointimal hyperplasia after balloon injury in the rat abdominal aorta. Am J. Physiol Heart Circ Physiol, 2004, 287: H1582-H1589.

　　本研究室可以提供共享的平台技术：

　　2D凝胶系统实时定量PCR、大鼠球囊拉伤模型、小鼠股动脉导丝拉伤模型、活性氧测定血管钙化模型、石蜡冰冻切片机、大鼠心梗模型

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