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Abrogation of MMP-9 gene protects against the development of retinopathy in diabetic mice by preventing mitochondrial damage.

Abstract In the development of diabetic retinopathy, mitochondrial dysfunction is considered to play an important role in the apoptosis of retinal capillary cells. Diabetes activates matrix metalloproteinase-9 (MMP-9) in the retina and its capillary cells, and activated MMP-9 becomes proapoptotic. The objective of this study is to elucidate the plausible mechanism by which active MMP-9 contributes to the mitochondrial dysfunction in the retina.
PMID
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Authors

Mayor MeshTerms

Apoptosis

Keywords
Journal Title diabetes
Publication Year Start




PMID- 21933988
OWN - NLM
STAT- MEDLINE
DCOM- 20111214
LR  - 20150129
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Linking)
VI  - 60
IP  - 11
DP  - 2011 Nov
TI  - Abrogation of MMP-9 gene protects against the development of retinopathy in
      diabetic mice by preventing mitochondrial damage.
PG  - 3023-33
LID - 10.2337/db11-0816 [doi]
AB  - OBJECTIVE: In the development of diabetic retinopathy, mitochondrial dysfunction 
      is considered to play an important role in the apoptosis of retinal capillary
      cells. Diabetes activates matrix metalloproteinase-9 (MMP-9) in the retina and
      its capillary cells, and activated MMP-9 becomes proapoptotic. The objective of
      this study is to elucidate the plausible mechanism by which active MMP-9
      contributes to the mitochondrial dysfunction in the retina. RESEARCH DESIGN AND
      METHODS: Using MMP-9 gene knockout (MMP-KO) mice, we investigated the effect of
      MMP-9 regulation on diabetes-induced increased retinal capillary cell apoptosis, 
      development of retinopathy, mitochondrial dysfunction and ultrastructure, and
      mitochondrial DNA (mtDNA) damage. To understand how diabetes increases
      mitochondrial accumulation of MMP-9, interactions between MMP-9 and chaperone
      proteins (heat shock protein [Hsp] 70 and Hsp60) were evaluated. The results were
      confirmed in the retinal mitochondria from human donors with diabetic
      retinopathy, and in isolated retinal endothelial cells transfected with MMP-9
      small interfering RNA (siRNA). RESULTS: Retinal microvasculature of MMP-KO mice, 
      diabetic for approximately 7 months, did not show increased apoptosis and
      pathology characteristic of retinopathy. In the same MMP-KO diabetic mice,
      activation of MMP-9 and dysfunction of the mitochondria were prevented, and
      electron microscopy of the retinal microvasculature region revealed normal
      mitochondrial matrix and packed lamellar cristae. Damage to mtDNA was protected, 
      and the binding of MMP-9 with Hsp70 or Hsp60 was also normal. As in the retina
      from wild-type diabetic mice, activation of mitochondrial MMP-9 and alterations
      in the binding of MMP-9 with chaperone proteins were also observed in the retina 
      from donors with diabetic retinopathy. In endothelial cells transfected with
      MMP-9 siRNA, high glucose-induced damage to the mitochondria and the chaperone
      machinery was ameliorated. CONCLUSIONS: Regulation of activated MMP-9 prevents
      retinal capillary cells from undergoing apoptosis by protecting mitochondrial
      ultrastructure and function and preventing mtDNA damage. Thus, MMP-9 inhibitors
      could have potential therapeutic value in preventing the development of diabetic 
      retinopathy by preventing the continuation of the vicious cycle of mitochondrial 
      damage.
FAU - Kowluru, Renu A
AU  - Kowluru RA
AD  - Kresge Eye Institute, Wayne State University, Detroit, Michigan, USA.
      [email protected]
FAU - Mohammad, Ghulam
AU  - Mohammad G
FAU - dos Santos, Julia M
AU  - dos Santos JM
FAU - Zhong, Qing
AU  - Zhong Q
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110920
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Chaperonin 60)
RN  - 0 (DNA, Mitochondrial)
RN  - 0 (HSP70 Heat-Shock Proteins)
RN  - 0 (Matrix Metalloproteinase Inhibitors)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
SB  - AIM
SB  - IM
MH  - Animals
MH  - *Apoptosis
MH  - Cells, Cultured
MH  - Chaperonin 60/metabolism
MH  - DNA Damage
MH  - DNA, Mitochondrial/chemistry
MH  - Diabetic Retinopathy/*metabolism/pathology/prevention & control
MH  - Enzyme Activation
MH  - Gene Silencing
MH  - HSP70 Heat-Shock Proteins/metabolism
MH  - Humans
MH  - Hyperglycemia/metabolism
MH  - Male
MH  - Matrix Metalloproteinase 9/genetics/*metabolism
MH  - Matrix Metalloproteinase Inhibitors
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Middle Aged
MH  - Mitochondria/*metabolism/ultrastructure
MH  - Molecular Targeted Therapy
MH  - Retina/*enzymology/ultrastructure
MH  - Retinal Vessels/*enzymology/pathology/ultrastructure
PMC - PMC3198054
OID - NLM: PMC3198054
EDAT- 2011/09/22 06:00
MHDA- 2011/12/15 06:00
CRDT- 2011/09/22 06:00
PHST- 2011/09/22 06:00 [entrez]
PHST- 2011/09/22 06:00 [pubmed]
PHST- 2011/12/15 06:00 [medline]
AID - db11-0816 [pii]
AID - 10.2337/db11-0816 [doi]
PST - ppublish
SO  - Diabetes. 2011 Nov;60(11):3023-33. doi: 10.2337/db11-0816. Epub 2011 Sep 20.