PMID- 32958629
OWN - NLM
STAT- MEDLINE
DCOM- 20201214
LR  - 20211102
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 375
IP  - 2
DP  - 2020 Nov
TI  - Targeted Injection of a Truncated Form of Tissue Inhibitor of Metalloproteinase 3 
      Alters Post-Myocardial Infarction Remodeling.
PG  - 296-307
LID - 10.1124/jpet.120.000047 [doi]
AB  - 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.
CI  - Copyright (c) 2020 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Lobb, David C
AU  - Lobb DC
AD  - 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.).
FAU - Doviak, Heather
AU  - Doviak H
AD  - 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.).
FAU - Brower, Gregory L
AU  - Brower GL
AD  - 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.).
FAU - Romito, Eva
AU  - Romito E
AD  - 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.).
FAU - O'Neill, Jason W
AU  - O'Neill JW
AD  - 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.).
FAU - Smith, Stephen
AU  - Smith S
AD  - 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.).
FAU - Shuman, James A
AU  - Shuman JA
AD  - 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.).
FAU - Freels, Parker D
AU  - Freels PD
AD  - 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.).
FAU - Zellars, Kia N
AU  - Zellars KN
AD  - 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.).
FAU - Freeburg, Lisa A
AU  - Freeburg LA
AD  - 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.).
FAU - Khakoo, Aarif Y
AU  - Khakoo AY
AD  - 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.).
FAU - Lee, TaeWeon
AU  - Lee T
AUID- ORCID: 0000-0001-9494-3517
AD  - 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.).
FAU - Spinale, Francis G
AU  - Spinale FG
AD  - 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.) cvctrc@uscmed.sc.edu.
LA  - eng
GR  - R01 HL111090/HL/NHLBI NIH HHS/United States
GR  - R01 HL113352/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20200921
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Cytokines)
RN  - 0 (Peptide Fragments)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-3)
RN  - 9007-34-5 (Collagen)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
SB  - IM
MH  - Amino Acid Sequence
MH  - Collagen/genetics
MH  - Cytokines/genetics
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Injections
MH  - Matrix Metalloproteinases/genetics
MH  - Myocardial Infarction/*pathology
MH  - Peptide Fragments/chemistry/*pharmacology
MH  - Protein Domains
MH  - RNA, Messenger/genetics
MH  - Tissue Inhibitor of Metalloproteinase-3/*chemistry/genetics
MH  - Ventricular Remodeling/*drug effects
PMC - PMC7589956
COIS- 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.
EDAT- 2020/09/23 06:00
MHDA- 2020/12/15 06:00
PMCR- 2021/11/01
CRDT- 2020/09/22 05:37
PHST- 2020/04/13 00:00 [received]
PHST- 2020/08/18 00:00 [accepted]
PHST- 2020/09/23 06:00 [pubmed]
PHST- 2020/12/15 06:00 [medline]
PHST- 2020/09/22 05:37 [entrez]
PHST- 2021/11/01 00:00 [pmc-release]
AID - jpet.120.000047 [pii]
AID - JPET_AR2020000047 [pii]
AID - 10.1124/jpet.120.000047 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2020 Nov;375(2):296-307. doi: 10.1124/jpet.120.000047. Epub 
      2020 Sep 21.