Local Hydrogel Release of Recombinant TIMP-3 Attenuates Adverse Left Ventricular Remodeling After Experimental Myocardial Infarction

被引：93

作者：

Eckhouse, Shaina R. ^{[1
]}

Purcell, Brendan P. ^{[2
]}

McGarvey, Jeremy R. ^{[3
]}

Lobb, David ^{[4
,5
]}

Logdon, Christina B. ^{[4
,5
]}

Doviak, Heather ^{[4
,5
]}

O'Neill, Jason W. ^{[6
]}

Shuman, James A. ^{[4
,5
]}

Novack, Craig P. ^{[4
,5
]}

Zellars, Kia N. ^{[4
,5
]}

Pettaway, Sara ^{[4
,5
]}

Black, Roy A. ^{[6
]}

Khakoo, Aarif ^{[6
]}

Lee, TaeWeon ^{[6
]}

Mukherjee, Rupak ^{[1
]}

Gorman, Joseph H. ^{[3
]}

Gorman, Robert C. ^{[3
]}

Burdick, Jason A. ^{[2
]}

Spinale, Francis G. ^{[4
,5
]}

机构：

[1] Med Univ S Carolina, Charleston, SC 29425 USA

[2] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA

[3] Univ Penn, Dept Surg, Gorman Cardiovasc Res Grp, Philadelphia, PA 19104 USA

[4] Univ S Carolina, Cardiovasc Translat Res Ctr, Sch Med, Columbia, SC 29208 USA

[5] William Jennings Bryan Dorn Veteran Affairs Med C, Columbia, SC 29208 USA

[6] Amgen Inc, Seattle, WA 91320 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2014年 / 6卷 / 223期

关键词：

MATRIX METALLOPROTEINASES; EXTRACELLULAR-MATRIX; TISSUE INHIBITORS; HEART-FAILURE; EXPANSION;

D O I：

10.1126/scitranslmed.3007244

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页数：10

共 26 条

[1]

TNF-α converting enzyme (TACE) is inhibited by TIMP-3 [J].