Local hydrogel release of recombinant TIMP-3 attenuates adverse left ventricular remodeling after experimental myocardial infarction.
Local hydrogel release of recombinant TIMP-3 attenuates adverse left ventricular remodeling after experimental myocardial infarction.
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DOI：
10.1126/scitranslmed.3007244
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发表时间：
2014-02-12
影响因子：
17.1
通讯作者：
Spinale FG
中科院分区：
文献类型：
--
作者：
Eckhouse SR;Purcell BP;McGarvey JR;Lobb D;Logdon CB;Doviak H;O'Neill JW;Shuman JA;Novack CP;Zellars KN;Pettaway S;Black RA;Khakoo A;Lee T;Mukherjee R;Gorman JH;Gorman RC;Burdick JA;Spinale FG
基质金属蛋白酶（MMPs）和基质金属蛋白酶组织抑制剂（TIMPs）之间的失衡有助于心肌梗死（MI）后发生的左心室（LV）重塑。然而，将这些观察结果转化为临床相关的治疗策略仍有待确定。本研究通过在大型动物模型中局部注射含有重组TIMP-3（rTIMP-3）的可降解透明质酸水凝胶来研究靶向TIMP增强。通过冠状动脉结扎在猪中诱导MI。然后将动物随机接受靶向水凝胶/rTIMP-3、单独水凝胶或盐水注射，并随访14天。没有MI诱导的仪器猪作为参考对照。多模式成像（荧光透视/超声心动图/磁共振成像）显示，与所有其他对照组相比，用rTIMP-3治疗的动物的LV射血分数改善，LV扩张减少，MI扩张减弱。水凝胶/rTIMP-3注射后MI区促炎细胞因子显著减少，平滑肌肌动蛋白含量增加，表明肌成纤维细胞增殖。这些结果首次证明了局部持续给予MMP抑制剂可以有效地中断MI后的不良重塑。
An imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) contributes to the left ventricle (LV) remodeling that occurs after myocardial infarction (MI). However, translation of these observations into a clinically relevant, therapeutic strategy remains to be established. The present study investigated targeted TIMP augmentation through regional injection of a degradable hyaluronic acid hydrogel containing recombinant TIMP-3 (rTIMP-3) in a large animal model. MI was induced in pigs by coronary ligation. Animals were then randomized to receive targeted hydrogel/rTIMP-3, hydrogel alone, or saline injection and followed for 14 days. Instrumented pigs with no MI induction served as referent controls. Multimodal imaging (fluoroscopy/ echocardiography/magnetic resonance imaging) revealed that LV ejection fraction was improved, LV dilation was reduced, and MI expansion was attenuated in the animals treated with rTIMP-3 compared to all other controls. A marked reduction in proinflammatory cytokines and increased smooth muscle actin content indicative of myofibroblast proliferation occurred in the MI region with hydrogel/rTIMP-3 injections. These results provide the first proof of concept that regional sustained delivery of an MMP inhibitor can effectively interrupt adverse post-MI remodeling.
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DOI：
10.1152/ajpheart.00402.2004
发表时间：
2005-02-01
影响因子：
4.8
作者：
Lovelock, JD;Baker, AH;Mann, DL
通讯作者：
Mann, DL
影响因子：
3
作者：
Baum J;Duffy HS
通讯作者：
Duffy HS
影响因子：
20.1
作者：
Frangogiannis NG
通讯作者：
Frangogiannis NG
影响因子：
20.1
作者：
Spinale FG;Janicki JS;Zile MR
通讯作者：
Zile MR
影响因子：
6
作者：
Lee, DC;Oz, MC;Ting, W
通讯作者：
Ting, W