Targeted Injection of a Truncated Form of Tissue Inhibitor of Metalloproteinase 3 Alters Post-MI Remodeling.
J Pharmacol Exp Ther. 2020 Sep 21;:
Authors: Lobb D, Doviak H, Brower G, Romito E, O’Neill J, Smith S, Shuman J, Freels P, Zellars K, Freeburg L, Khakoo A, Lee T, Spinale FG
Background : Infarct expansion can occur after myocardial infarction (MI), which leads to adverse left ventricular (LV) remodeling and failure. An imbalance between matrix metalloproteinase (MMP) induction and tissue inhibitors of MMPs (TIMPs) can accelerate this process. Past studies have shown different biological effects of TIMP-3, which may depend upon specific domains within the TIMP-3 molecule This study tested the hypothesis that differential effects of direct myocardial injections of either a full length recombinant TIMP-3 (F-TIMP-3) or a truncated form encompassing the N-terminal region (N-TIMP-3) could be identified post-MI. Methods/Results : MI was induced in pigs and randomized for MI injections (30 mg) and received targeted injections within the MI region of F-TIMP-3 (n=8), N-TIMP-3 (n=9), or saline injection (MI-only, n=11). At 14 days post-MI, LV ejection fraction fell post-MI but remained higher in both TIMP-3 groups. Tumor necrosis factor and interleukin-10 mRNA increased by over 10-fold in the MI only and N-TIMP-3 groups but were reduced with F-TIMP-3 at this post-MI time point. Conclusion : Direct MI injection of either a full length or truncated form of TIMP-3 is sufficient to favorably alter the course of post-MI remodeling. The functional and differential relevance of TIMP-3 domains has been established in-vivo since the TIMP-3 constructs demonstrated different MMP/cytokine expression profiles. These translational studies identify a unique and more specific therapeutic strategy to alter the course of LV remodeling and dysfunction following MI. Significance Statement Using different TIMP-3 formulations, when injected into the MI region, slowed the progression of indices of LV failure, suggesting that the N terminus of TIMP-3 is sufficient to attenuate early adverse functional events post-MI. The F-TIMP-3 injections but not N-TIMP-3 injections reduced relative indices of inflammation at the mRNA level, suggesting that the C-terminus region affects other biological pathways. These unique proof of concept studies demonstrate the feasibility of using recombinant small molecules to selectively interrupt adverse LV remodeling post-MI.
PMID: 32958629 [PubMed – as supplied by publisher]