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3.1 MMP9與糖尿病動脈粥樣硬化
大血管病變是2型糖尿病的主要慢性并發(fā)癥,也是2型糖尿病死亡的主要原因,其基本病理變化是動脈粥樣硬化。動脈粥樣硬化過程中,血管內(nèi)皮細胞、平滑肌細胞、巨噬細胞、泡沫細胞均能合成和分泌MMP9,尤以巨噬細胞作用最強,MMP9降解基底膜,利于單核細胞入侵,加速oxLDL滲透。使糖尿病動脈粥樣斑塊較非糖尿病者更不穩(wěn)定。眾多研究表明2型糖尿病合并AS病變者MMP9水平較單純2型糖尿病者或單純AS者明顯升高。在動物模型中，Uemura等[14]用明膠酶譜及Western印跡分析、電子順磁共振等檢測發(fā)現(xiàn),不管是1型還是2型嚙齒類糖尿病動物模型,其血管組織和血漿中MMP9均明顯升高。Camp等[15]用酶譜分析方法觀察到與非糖尿病野生型鼠相比,糖尿病野生鼠血漿和左心室中MMP9的活性升高。而對糖尿病鼠而言,不管是野生型還是MMP9基因敲除鼠,心臟組織型TIMP的濃度均減少。而且MMP9活性的升高與心臟內(nèi)皮功能紊亂密切相關(guān)。在人體，李佳等[16]報道, 2型糖尿病患者血清MMP9含量明顯高于非糖尿病患者,治療4周時,MMP9水平即明顯下降,且其降低與HbA1c的降低呈正相關(guān)。在分子水平，Death等[17]也發(fā)現(xiàn)高糖培養(yǎng)可導致內(nèi)皮細胞和單核細胞MMP/TIMP系統(tǒng)表達失衡,特別是可使單核巨噬細胞MMP9表達和活性升高(P<0.05),加速糖尿病AS的形成并降低斑塊穩(wěn)定性。另外MMPs基因多態(tài)性與糖尿病大血管病變的發(fā)生有密切關(guān)系。劉寬芝等[18]發(fā)現(xiàn)與對照組和2型糖尿病組相比,大血管病變組的T等位基因和TT等位基因型頻率顯著高于健康對照組和無并發(fā)癥組。
糖尿病引起MMP9升高的機制目前研究主要集中在氧化低密度脂蛋白(OxLDL)和某些細胞因子的作用。糖尿病機體中低密度脂蛋白(LDL)的糖化和氧化明顯增加，OxLDL可直接上調(diào)單核細胞源性的巨噬細胞中MMP9的表達,而高密度脂蛋白(HDLC)可阻斷OxLDL的上述效應。2型糖尿病患者往往存在不同程度的IR,使高血壓的發(fā)病率顯著上升,長期的高血壓可使血管內(nèi)皮功能受損,加速糖尿病血管病變的發(fā)生、發(fā)展。陳雅靜等[19]報道, 2型糖尿病患者血清MMP9含量明顯升高,其升高程度與血壓呈正相關(guān)。糖尿病引起MMP9升高的具體機制的研究尚處于初步階段，有待進一步探索。
【參考文獻】
[1] Brunkhorst F M, Eberhard O K, Brunkhorst R. Discrimination of infectious and noninfectious causes of early acute respiratory distress syndrome by procalcitonin [J]. Crit Care Med, 1999, 27(10): 21722176.
[2] Rajavashish T B, Xu Xp, Jovinge S. Membrance type 1 matrix metalloproteinase expression in human atherosclerotic plaques:evidence for activation by proinflammatory mediators[J]. Circulation, 1999, 99: 31033109.
[3] Sopata I, Dancewicz A M. Presence of a gelatinspecific proteinase and its latent form in human leucocytes[J]. Biochim BiophysActa, 1974, 370(2): 510523.
[4] Robert Visse, Hideaki Nagase. Matrix metalloproteinases and tissue inhibitors of metalloproteinases structure function and biochemistry[J]. Circ Res, 2003, 9(8):827 839.
[5] Sheu J R, Fong T H, Liu C M,et al. Expression of matrix metalloproteinase9 in human platelets: regulation of platelet activation in vitro and in vivo studies[J].Br J Harmacol, 2004, 143(1): 193201.
[6] Wilson S R,Gallagher S,Warpeha K,et al.Amplification of MMP2 and MMP9 production by prostate cancer cell linesvia activation of protease activated receptors[J].Prostate, 2004, 60(2): 16874醫(yī)學全.在線m.zxtf.net.cn.
[7] Galis Z S, Muszynski M, Sukhova G K, et al. Cytokinestimulated human vascular smooth muscle cells synthesize acomplement of enzymes required for extracellura matrix digestion[J]. Circ Res, 1994, 75 : 181189.
[8] Mason D P,Kenagy R D,Hasenstab D, et al. Matrix metalloproteinases 9 over expression enhances vascular smooth muscle cellmigration and alters remodeling in the injured rat carotid artery[J].Circ Res, 1999, 85(12): 11791185.
[9] Cho A,Reidy M A.Matrixmetalloproteinases9 isnecessary for the regulation of smoothmuscle cell replication andmigration after arterial injury[J].Circ Res,2002, 91(9): 845851.
[10] Brown D L,Hibbs M S,Kearney M,et al. Identification of 92 kD gelatinase in human coronary atherosclerotic lesions. Association of active enzyme synthesis with unstable angina [J]. Circulation,1995, 91(8): 21252131.
[11] Gough P J,Gomez I G,Wille P T.Macrophage expression of active MMP9 induceacute plaque disruption in apoEdeficientmice[J].Clin Invest, 2006, 116(1):5969.
[12] Loftus I M,Naylor A R, Goodall S,et al. Increased matrix metalloproteinase9 activity in unstable carotid plaques.A potential role in acute plaque disruption[J]. Stroke, 2000, 31(1): 4047.
[13] Kai H, Ikeda H,Yasukawa H,et al. Peripheral blood levels of matrix metalloproteases2 and9 are elevated in patients with acute coronary syndromes[J]. J Am Coll Cardiol, 1998, 32 ( 2 ):368372.
[14] Uemura S,Matsushita H,Li W,et al.Diabetes mellitus enhances vascular matrix metalloproteinase activity:role of oxidative stress[J]. Circ Res,2001,12:12911298.
[15] GiamarellosBourboulis E J, Grecka P, Poulakou G, et a1.Assessment of procalcitonin as a diagnostic marker of underling infection in patient swith febrile neutrepenia [J]. Clin Infect Dis,2001, 32 (12): 17181725.
[16] Torbe A, Czajka R. Procalcitonin in cervicovaginal secretion in pregnancies complicated by preterm laborA preliminary report[J].European Journal of Obstetrics, Gynecology and Reproductive Biology, 2004,116(2):245.
[17] DEATH A K,FISHER E J,MCGRATH K C,et al.High Glucose Alters Matrix Metalloproteinase Expression in Two Key Vascular Cells:Potential Impact on Atherosclerosis in Diabetes [J].Atherosclerosis, 2003, 168(2):263269.
[18] 許瑞英,董俊華,楊興季,等.血清降鈣素原水平對泌尿系感染定位診斷價值的研究[J].山東大學學報(醫(yī)學版),2003, 41 (5): 536.
[19] Bitkover C Y, Hansson L O, Valen G, et al. Effectsofcardiac surgery on some clinically used inflammationmarkers and procalcitonin [J]. Scand Cardiovasc J, 2000, 34 (3): 307314.
