PMID- 18055551
OWN - NLM
STAT- MEDLINE
DCOM- 20080208
LR  - 20211020
IS  - 0002-9440 (Print)
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Linking)
VI  - 171
IP  - 6
DP  - 2007 Dec
TI  - Amelioration of coxsackievirus B3-mediated myocarditis by inhibition of tissue 
      inhibitors of matrix metalloproteinase-1.
PG  - 1762-73
AB  - Coxsackievirus B3 (CVB3) is a major cause of acute myocarditis, a serious 
      condition that is refractory to treatment. Myocardial damage results in tissue 
      remodeling that, if too extensive, may contribute to disease. Remodeling is 
      achieved by extracellular proteolysis mediated by the matrix metalloproteinases 
      (MMPs), and MMP activity is counterbalanced by tissue inhibitors of MMPs (TIMPs). 
      We show herein that TIMP-1 expression is induced in the myocardium by CVB3 
      infection. Surprisingly, TIMP-1 knockout mice exhibited a profound attenuation of 
      myocarditis, with increased survival. The amelioration of disease in TIMP-1 
      knockout mice was not attributable to either an altered T-cell response to the 
      virus or to reduced viral replication. These data led us to propose a novel 
      function for TIMP-1: its highly localized up-regulation might arrest the 
      MMP-dependent migration of inflammatory cells at sites of infection, thereby 
      anatomically focusing the adaptive immune response. The benefits of TIMP-1 
      blockade in treating viral myocarditis were confirmed by administering, to 
      wild-type animals, TIMP-1-specific siRNA or polyclonal antisera, both of which 
      diminished CVB3-induced myocarditis. These unexpected findings indicate that 
      increased TIMP-1 expression exacerbates, rather than ameliorates, CVB3-induced 
      myocarditis and, thus, that TIMP-1 may represent a target for the treatment of 
      virus-induced heart disease.
FAU - Crocker, Stephen J
AU  - Crocker SJ
AD  - Molecular and Integrative Neurosciences Dept., SP30-2110, The Scripps Research 
      Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA. .
FAU - Frausto, Ricardo F
AU  - Frausto RF
FAU - Whitmire, Jason K
AU  - Whitmire JK
FAU - Benning, Nicola
AU  - Benning N
FAU - Milner, Richard
AU  - Milner R
FAU - Whitton, J Lindsay
AU  - Whitton JL
LA  - eng
GR  - R01 AI042314/AI/NIAID NIH HHS/United States
GR  - AI-42314/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20071130
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - 0 (Immune Sera)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-1)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Coxsackievirus Infections/*complications
MH  - *Enterovirus B, Human
MH  - Immune Sera/pharmacology
MH  - Lymphocyte Activation
MH  - Mice
MH  - Mice, Knockout
MH  - Myocarditis/*metabolism/pathology/*virology
MH  - RNA, Small Interfering/pharmacology
MH  - T-Lymphocytes/immunology
MH  - Tissue Inhibitor of Metalloproteinase-1/*antagonists & 
      inhibitors/genetics/metabolism
MH  - Up-Regulation
PMC - PMC2111101
EDAT- 2007/12/07 09:00
MHDA- 2008/02/09 09:00
PMCR- 2008/06/01
CRDT- 2007/12/07 09:00
PHST- 2007/12/07 09:00 [pubmed]
PHST- 2008/02/09 09:00 [medline]
PHST- 2007/12/07 09:00 [entrez]
PHST- 2008/06/01 00:00 [pmc-release]
AID - S0002-9440(10)62439-X [pii]
AID - 10.2353/ajpath.2007.070179 [doi]
PST - ppublish
SO  - Am J Pathol. 2007 Dec;171(6):1762-73. doi: 10.2353/ajpath.2007.070179. Epub 2007 
      Nov 30.