PMID- 32035727
OWN - NLM
STAT- MEDLINE
DCOM- 20210506
LR  - 20210506
IS  - 1557-3117 (Electronic)
IS  - 1053-2498 (Linking)
VI  - 39
IP  - 4
DP  - 2020 Apr
TI  - AAV-mediated TIMP-1 overexpression in aortic tissue reduces the severity of 
      allograft vasculopathy in mice.
PG  - 389-398
LID - S1053-2498(20)31356-5 [pii]
LID - 10.1016/j.healun.2020.01.1338 [doi]
AB  - BACKGROUND: Allograft vasculopathy (AV) is the primary limiting factor for 
      long-term graft survival. An increased activity of matrix metalloproteinases 
      (MMPs) contributes to neointima formation in AV and represents a potential 
      therapeutic target. Adeno-associated virus (AAV)-mediated gene therapy comprises 
      a potentially benign vector model for the long-term expression of MMP 
      antagonists. METHODS: Aortic allografts from DBA/2 mice were incubated with 
      control buffer, AAV-enhanced green fluorescence protein (EGFP), or tissue 
      inhibitor of metalloproteinases 1 (TIMP-1)-loaded AAV (AAV-TIMP-1) and 
      transplanted into the infrarenal aorta of C57BL/6 mice. Cyclosporine A (10 mg/kg 
      body weight) was administered daily. Explantation as well as histomorphometric 
      and immunohistochemical evaluation was performed after 30 days. Matrix 
      metalloproteinase (MMP) activity was visualized by gelatin in situ zymography. 
      RESULTS: Intima-to-media area ratio and neointima formation were significantly 
      reduced in the AAV-TIMP-1 treatment group compared with those in the control 
      group (by 40%; p < 0.001) and the AAV-EGFP group (by 38.2%; p < 0.001). TIMP-1 
      overexpression positively affected several pathomechanisms for the development of 
      AV both in vitro and in vivo as compared to that in the control groups: 
      endothelium integrity was preserved as shown by zona occludens 1 and occludin 
      staining; MMP9 expression and activity were significantly reduced (p = 0.01); and 
      smooth muscle cell migration was significantly reduced as smooth muscle actin 
      positive cells predominantly remained in the aortic media in the treatment group 
      (p = 0.001). Moreover, macrophage infiltration was markedly reduced by 49% in the 
      AAV-TIMP-1 group (p < 0.001). CONCLUSION: Immediate post-harvesting allograft 
      incubation with AAV-TIMP-1 reduces neointima formation and macrophage 
      infiltration, constituting a possible adjunct therapeutic strategy to preserve 
      graft function after transplantation.
CI  - Copyright (c) 2020 International Society for Heart and Lung Transplantation. 
      Published by Elsevier Inc. All rights reserved.
FAU - Remes, Anca
AU  - Remes A
AD  - Department of Internal Medicine III, University Hospital Kiel, Kiel, Germany.
FAU - Franz, Maximilian
AU  - Franz M
AD  - Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, 
      Germany.
FAU - Zaradzki, Marcin
AU  - Zaradzki M
AD  - Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, 
      Germany.
FAU - Borowski, Christopher
AU  - Borowski C
AD  - Department of Internal Medicine III, University Hospital Kiel, Kiel, Germany.
FAU - Frey, Norbert
AU  - Frey N
AD  - Department of Internal Medicine III, University Hospital Kiel, Kiel, Germany.
FAU - Karck, Matthias
AU  - Karck M
AD  - Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, 
      Germany.
FAU - Kallenbach, Klaus
AU  - Kallenbach K
AD  - INCCI HaerzZenter, Department of Cardiac Surgery, Luxembourg, Luxembourg.
FAU - Muller, Oliver J
AU  - Muller OJ
AD  - Department of Internal Medicine III, University Hospital Kiel, Kiel, Germany.
FAU - Wagner, Andreas H
AU  - Wagner AH
AD  - Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, 
      Germany.
FAU - Arif, Rawa
AU  - Arif R
AD  - Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, 
      Germany. Electronic address: rawa.arif@med.uni-heidelberg.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200130
PL  - United States
TA  - J Heart Lung Transplant
JT  - The Journal of heart and lung transplantation : the official publication of the 
      International Society for Heart Transplantation
JID - 9102703
RN  - 0 (Tissue Inhibitor of Metalloproteinase-1)
RN  - 63231-63-0 (RNA)
SB  - IM
MH  - Allografts
MH  - Animals
MH  - Aorta, Thoracic/metabolism/pathology/*transplantation
MH  - Blotting, Western
MH  - Cells, Cultured
MH  - Dependovirus/*enzymology
MH  - Disease Models, Animal
MH  - *Gene Expression Regulation
MH  - Graft Rejection/enzymology/*genetics/pathology
MH  - Humans
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred DBA
MH  - RNA/genetics
MH  - Tissue Inhibitor of Metalloproteinase-1/biosynthesis/*genetics
MH  - Tunica Intima/*metabolism/pathology
OTO - NOTNLM
OT  - adeno-associated virus
OT  - allograft vasculopathy
OT  - gene therapy
OT  - matrix metalloproteinases
OT  - tissue inhibitor of metalloproteinases
EDAT- 2020/02/10 06:00
MHDA- 2021/05/07 06:00
CRDT- 2020/02/10 06:00
PHST- 2019/10/09 00:00 [received]
PHST- 2020/01/16 00:00 [revised]
PHST- 2020/01/24 00:00 [accepted]
PHST- 2020/02/10 06:00 [pubmed]
PHST- 2021/05/07 06:00 [medline]
PHST- 2020/02/10 06:00 [entrez]
AID - S1053-2498(20)31356-5 [pii]
AID - 10.1016/j.healun.2020.01.1338 [doi]
PST - ppublish
SO  - J Heart Lung Transplant. 2020 Apr;39(4):389-398. doi: 
      10.1016/j.healun.2020.01.1338. Epub 2020 Jan 30.