Identification of myocardial Tissue Tactors of ventricular remodeling

(1)组织金属蛋白酶及其组织抑制物(TIMP)净激活对心肌组织基质的动态调节：以Dahl盐敏感型高血压心力衰竭大鼠为模型，比较心力衰竭形成前后心肌组织中MMPs和TIMP活性的变化。随着心力衰竭的转变，扫描电子显微镜清楚地显示了与相对(净)控制基质金属蛋白酶活性有关的细胶原网络的破坏。(2)外源性TIMP的供应抑制了心室重构：我们用TIMP-2抑制剂ONO-4817长期处理这些动物。通过这种治疗，大鼠存活时间更长，其左心功能保持正常，没有重塑。因此，这种干预措施可能是遇到心脏重塑患者的一种辅助治疗。(3)心力衰竭组织中基质金属蛋白酶/组织金属蛋白酶抑制剂的上游调节：在血管紧张素II受体阻滞剂valsaltan的支持下，长期使用ONO-4817的动物显示出类似的存活率。因此，可以想象RAS可能直接调节基质金属蛋白酶/TIMP的活性，而完全抑制RAS可能足以抑制细胞外基质的降解和心室重构。

(1) Dynamic regulation of myocardial tissue matrix by net activations of tissue mettaloproteinases (MMP) and their tissue inhibitors (TIMP) : Using Dahl salt-sensitive hypertension rats with heart failure transition, we compared tissue MMP versus TIMP activations before and after the development of heart failure. Along with heart failure transition, the scanning electron microscope clearly demonstrated the destruction of the thin collagen network that was associated with relative (net) domination of MMP activities.(2) Exogenous supply of a TIMP inhibits the ventricular remodeling: We chronically treated these animals with ONO-4817, a TIMP-2 inhibitor. With this treatment, the rats survived longer, and their LV function remained normal without the remodeling. Therefore, such an intervention could be an adjuvant therapy for patients encountering the ventricular remodeling.(3) Upstream regulation of MMP/TIMP in the tissue of failing hearts: Chronic treatment of the animals with ONO-4817 on the top of an angiotensin II receptor blocker, valsaltan, showed the similar survival. Thus, it is conceivable that the RAS may directly regulates the MMP/TIMP activities, and full inhibition of RAS may be enough to suppress the Extracellular matrix degradation and ventricular remodeling.