基质金属蛋白酶MMPs与心室重塑的关系及相关治疗参考课件.ppt

1、123456789Figure 21-18 The regulation of extracellular matrix degradation is determined by the balance between the activity of matrix metalloproteinases(MMPs)and their tissue inhibitors(TIMPs).Both an increase in MMP activity and a decrease in TIMP activity have been observed in failing myocardium fr

2、om patients.Theoretically,such an increase in the MMP/TIMP ratio could contribute to depletion of the fibrillar collagen struts that tether myocytes together and might thus contribute to chamber dilation.Conversely,an increase in extracellular matrix accumulation,which might occur as the result of a

3、 decrease in the MMP/TIMP ratio or an increase in matrix synthesis,could contribute to chamber stiffness and abnormal relaxation.(From Sawyer DB,Colucci WS:Molecular and cellular events in myocardial hypertrophy and failure.In Colucci WS ed:Atlas of Heart Failure:Cardiac Function and Dysfunction.3rd

4、 ed.Philadelphia,Current Medicine,2002,p 7.8.)10心肌梗塞 压力负荷增高 MMPs升高 室壁变薄心室扩张心功能下降 TIMPs MMP-TIMP复合物 高MMPs/TIMPs 加剧心室重塑低MMPs/TIMPs 改善111213步骤一实验结步骤一实验结果果:MMP-2蛋白在蛋白在心梗心梗1周时明显周时明显增加增加;MMP-9蛋白在蛋白在心梗心梗1周和周和2周周时明显增加时明显增加;TIMP-1在心梗在心梗各时间点均明各时间点均明显减少显减少14步骤二及步骤三的实验结果?1516171819202122心力衰竭神经激素异常长期神经激素激活细胞因子水、

5、钠潴留水肿 肺充血血流动力学异常冠脉及全身血管收缩心肌耗氧量增加心肌氧供应降低心肌细胞功能障碍和坏死心室重塑和功能恶化进展疾病进展生存率降低血管紧张素和儿茶酚胺毒性作用心肌细胞凋亡过度氧化23 Matrix metalloproteinase(MMP)regulation.Four mechanisms are shown:(1)regulation of synthesis by growth factors or cytokines.(2)inhibition of synthesis by corticosteroids or TGF-.(3)regulation of the acti

6、vation of the secreted but inactive precursors.(4)(4)blockage of the enzymes by specific tissue inhibitors of metalloproteinase(TIMPs).(Modified from Matrisian LM:Metalloproteinases and their inhibitors in matrix remodeling.Trends Genet 6:122,1990,with permission from Elsevier Science.)24Activation

7、Mechanisms of proMMPs.Most secreted-type proMMPs,such as proMMP-3,are activated extracellularly by many proteinases(extracellular activation).Furin-activated secreted proMMPs,including proMMP-11,and proMT-MMPs such as proMT1-MMP are intracellularly activated through removal of the propeptides(arrowh

8、eads)by the action of proprotein convertases such as furin(intracellular activation).ProMMP-2 is activated on the cell membrane by MT1-MMP;this activation requires trimolecular complex of MT1-MMP/TIMP-2/proMMP-2 and dimerization of MT1-MMP(pericellular activation).Ct,C-terminal domain of TIMP-2;F,furin-recognition site.2526型胶原占心肌胶原总量的90%!27The Domain Structures of Two Types of MMPs(Secreted-type MMP and Membrane-anchored MMP)28