title: Local hydrogel release of recombinant TIMP-3 attenuates adverse left ventricular remodeling after experimental myocardial infarction.
abstract: 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.
authors: Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
authors: Shaina R
authors: SR
authors: Eckhouse
authors: Brendan P
authors: BP
authors: Purcell
authors: Jeremy R
authors: JR
authors: McGarvey
authors: David
authors: D
authors: Lobb
authors: Christina B
authors: CB
authors: Logdon
authors: Heather
authors: H
authors: Doviak
authors: Jason W
authors: JW
authors: O'Neill
authors: James A
authors: JA
authors: Shuman
authors: Craig P
authors: CP
authors: Novack
authors: Kia N
authors: KN
authors: Zellars
authors: Sara
authors: S
authors: Pettaway
authors: Roy A
authors: RA
authors: Black
authors: Aarif
authors: A
authors: Khakoo
authors: Taeweon
authors: T
authors: Lee
authors: Rupak
authors: R
authors: Mukherjee
authors: Joseph H
authors: JH
authors: Gorman
authors: Robert C
authors: RC
authors: Gorman
authors: Jason A
authors: JA
authors: Burdick
authors: Francis G
authors: FG
authors: Spinale
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000008:administration & dosage / Q000737:chemistry*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use*; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*
chemical_list: D019717:Tissue Inhibitor of Metalloproteinase-3; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate