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Targeted Injection of a Truncated Form of Tissue Inhibitor of Metalloproteinase 3 Alters Post-Myocardial Infarction Remodeling.
Lobb, David C; Doviak, Heather; Brower, Gregory L; Romito, Eva; O'Neill, Jason W; Smith, Stephen; Shuman, James A; Freels, Parker D; Zellars, Kia N; Freeburg, Lisa A; Khakoo, Aarif Y; Lee, TaeWeon; Spinale, Francis G.
Afiliação
  • Lobb DC; 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
  • Doviak H; 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
  • Brower GL; 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
  • Romito E; 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
  • O'Neill JW; 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
  • Smith S; 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
  • Shuman JA; 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
  • Freels PD; 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
  • Zellars KN; 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
  • Freeburg LA; 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
  • Khakoo AY; 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
  • Lee T; 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
  • Spinale FG; 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 Pharmacol Exp Ther ; 375(2): 296-307, 2020 11.
Article em En | MEDLINE | ID: mdl-32958629
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fragmentos de Peptídeos / Inibidor Tecidual de Metaloproteinase-3 / Remodelação Ventricular / Infarto do Miocárdio Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fragmentos de Peptídeos / Inibidor Tecidual de Metaloproteinase-3 / Remodelação Ventricular / Infarto do Miocárdio Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article