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会计学1基质金属蛋白酶基质金属蛋白酶MMPs与心室重塑的关系与心室重塑的关系及相关治疗及相关治疗第1页/共28页第2页/共28页第3页/共28页第4页/共28页第5页/共28页第6页/共28页第7页/共28页第8页/共28页Figure 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 from 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 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 ed. Philadelphia, Current Medicine, 2002, p 7.8.)第9页/共28页心肌梗塞 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 改善第10页/共28页第11页/共28页第12页/共28页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周时明周时明显增加显增加;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第13页/共28页步骤二及步骤三的实验结果 ?第14页/共28页第15页/共28页第16页/共28页第17页/共28页第18页/共28页第19页/共28页第20页/共28页第21页/共28页心力衰竭神经激素异常长期神经激素激活细胞因子水、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第22页/共28页 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 activation of the secreted but inactive precursors.(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.)第23页/共28页Activation 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 (arrowheads) 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.第24页/共28页第25页/共28页心室腔. (4)控制心肌细胞过度伸长与回缩.型胶原占心肌胶原总量的90% !第26页/共28页The Domain Structures of Two Types of MMPs (Secreted-type MMP and Membrane-anchored MMP) 第27页/共28页
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