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Research ArticleCardiovascular

Targeted Injection of a Truncated Form of Tissue Inhibitor of Metalloproteinase 3 Alters Post–Myocardial Infarction Remodeling

David C. Lobb, Heather Doviak, Gregory L. Brower, Eva Romito, Jason W. O’Neill, Stephen Smith, James A. Shuman, Parker D. Freels, Kia N. Zellars, Lisa A. Freeburg, Aarif Y. Khakoo, TaeWeon Lee and Francis G. Spinale
Journal of Pharmacology and Experimental Therapeutics November 2020, 375 (2) 296-307; DOI: https://doi.org/10.1124/jpet.120.000047
David C. Lobb
Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (D.C.L., H.D., G.L.B., E.R., J.A.S., P.D.F., K.N.Z., L.A.F., F.G.S.) and Amgen, Metabolic Disorders, South San Francisco, California (J.W.O., S.S., A.Y.K., T.L.)
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Heather Doviak
Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (D.C.L., H.D., G.L.B., E.R., J.A.S., P.D.F., K.N.Z., L.A.F., F.G.S.) and Amgen, Metabolic Disorders, South San Francisco, California (J.W.O., S.S., A.Y.K., T.L.)
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Gregory L. Brower
Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (D.C.L., H.D., G.L.B., E.R., J.A.S., P.D.F., K.N.Z., L.A.F., F.G.S.) and Amgen, Metabolic Disorders, South San Francisco, California (J.W.O., S.S., A.Y.K., T.L.)
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Eva Romito
Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (D.C.L., H.D., G.L.B., E.R., J.A.S., P.D.F., K.N.Z., L.A.F., F.G.S.) and Amgen, Metabolic Disorders, South San Francisco, California (J.W.O., S.S., A.Y.K., T.L.)
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Jason W. O’Neill
Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (D.C.L., H.D., G.L.B., E.R., J.A.S., P.D.F., K.N.Z., L.A.F., F.G.S.) and Amgen, Metabolic Disorders, South San Francisco, California (J.W.O., S.S., A.Y.K., T.L.)
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Stephen Smith
Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (D.C.L., H.D., G.L.B., E.R., J.A.S., P.D.F., K.N.Z., L.A.F., F.G.S.) and Amgen, Metabolic Disorders, South San Francisco, California (J.W.O., S.S., A.Y.K., T.L.)
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James A. Shuman
Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (D.C.L., H.D., G.L.B., E.R., J.A.S., P.D.F., K.N.Z., L.A.F., F.G.S.) and Amgen, Metabolic Disorders, South San Francisco, California (J.W.O., S.S., A.Y.K., T.L.)
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Parker D. Freels
Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (D.C.L., H.D., G.L.B., E.R., J.A.S., P.D.F., K.N.Z., L.A.F., F.G.S.) and Amgen, Metabolic Disorders, South San Francisco, California (J.W.O., S.S., A.Y.K., T.L.)
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Kia N. Zellars
Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (D.C.L., H.D., G.L.B., E.R., J.A.S., P.D.F., K.N.Z., L.A.F., F.G.S.) and Amgen, Metabolic Disorders, South San Francisco, California (J.W.O., S.S., A.Y.K., T.L.)
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Lisa A. Freeburg
Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (D.C.L., H.D., G.L.B., E.R., J.A.S., P.D.F., K.N.Z., L.A.F., F.G.S.) and Amgen, Metabolic Disorders, South San Francisco, California (J.W.O., S.S., A.Y.K., T.L.)
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Aarif Y. Khakoo
Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (D.C.L., H.D., G.L.B., E.R., J.A.S., P.D.F., K.N.Z., L.A.F., F.G.S.) and Amgen, Metabolic Disorders, South San Francisco, California (J.W.O., S.S., A.Y.K., T.L.)
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TaeWeon Lee
Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (D.C.L., H.D., G.L.B., E.R., J.A.S., P.D.F., K.N.Z., L.A.F., F.G.S.) and Amgen, Metabolic Disorders, South San Francisco, California (J.W.O., S.S., A.Y.K., T.L.)
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Francis G. Spinale
Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (D.C.L., H.D., G.L.B., E.R., J.A.S., P.D.F., K.N.Z., L.A.F., F.G.S.) and Amgen, Metabolic Disorders, South San Francisco, California (J.W.O., S.S., A.Y.K., T.L.)
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Abstract

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 biologic 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. MI was induced in pigs that were 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. 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 after MI.

SIGNIFICANCE STATEMENT Using different formulations of tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), when injected into the myocardial infarction (MI) region, slowed the progression of indices of left ventricular (LV) failure, suggesting that the N terminus of TIMP-3 is sufficient to attenuate early adverse functional events post-MI. Injections of full-length recombinant TIMP-3, but not of the N-terminal region of TIMP-3, reduced relative indices of inflammation at the mRNA level, suggesting that the C-terminal 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.

Footnotes

    • Received April 13, 2020.
    • Accepted August 18, 2020.
  • This work was supported by National Institutes of Health National Heart, Lung, and Blood Institute [Grants HL111090 and HL113352], a Merit Award from the Veterans’ Affairs Health Administration, and a basic research grant from Amgen, Inc.

  • J.W.O., S.S., A.Y.K., and T.L. are employees of Amgen Inc. that manufacture drugs for a wide range of diseases, including cardiovascular disease. The other authors declare that they have no competing interests. The recombinant TIMP-3 formulations were furnished as an material transfer agreement from Amgen to F.G.S.

  • https://doi.org/10.1124/jpet.120.000047.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 375 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 375, Issue 2
1 Nov 2020
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Research ArticleCardiovascular

TIMP-3 Domains and Post-MI Remodeling

David C. Lobb, Heather Doviak, Gregory L. Brower, Eva Romito, Jason W. O’Neill, Stephen Smith, James A. Shuman, Parker D. Freels, Kia N. Zellars, Lisa A. Freeburg, Aarif Y. Khakoo, TaeWeon Lee and Francis G. Spinale
Journal of Pharmacology and Experimental Therapeutics November 1, 2020, 375 (2) 296-307; DOI: https://doi.org/10.1124/jpet.120.000047

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Research ArticleCardiovascular

TIMP-3 Domains and Post-MI Remodeling

David C. Lobb, Heather Doviak, Gregory L. Brower, Eva Romito, Jason W. O’Neill, Stephen Smith, James A. Shuman, Parker D. Freels, Kia N. Zellars, Lisa A. Freeburg, Aarif Y. Khakoo, TaeWeon Lee and Francis G. Spinale
Journal of Pharmacology and Experimental Therapeutics November 1, 2020, 375 (2) 296-307; DOI: https://doi.org/10.1124/jpet.120.000047
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