PubTransformer

A site to transform Pubmed publications into these bibliographic reference formats: ADS, BibTeX, EndNote, ISI used by the Web of Knowledge, RIS, MEDLINE, Microsoft's Word 2007 XML.

Regulation of matrix metalloproteinase-9 by epigenetic modifications and the development of diabetic retinopathy.

Abstract Diabetes activates retinal matrix metalloproteinase-9 (MMP-9), and MMP-9 damages the mitochondria and augments capillary cell apoptosis. Our aim is to elucidate the mechanism responsible for MMP-9 activation. Histone modifications and recruitment of the nuclear transcriptional factor-κB (p65 subunit) at the MMP-9 promoter and the activity of lysine-specific demethylase 1 (LSD1) were measured in the retina from streptozotocin-induced diabetic rats. The role of LSD1 in MMP-9 activation was investigated in isolated retinal endothelial cells transfected with LSD1 small interfering RNA (siRNA). The results were confirmed in the retina from human donors with diabetic retinopathy. Diabetes decreased histone H3 dimethyl lysine 9 (H3K9me2) and increased acetyl H3K9 (Ac-H3K9) and p65 at the retinal MMP-9 promoter. LSD1 enzyme activity and its transcripts were elevated. LSD1 siRNA ameliorated the glucose-induced decrease in H3K9me2 and increase in p65 at the MMP-9 promoter, and prevented MMP-9 activation, mitochondrial damage, and cell apoptosis. Human donors with diabetic retinopathy had similar epigenetic changes at the MMP-9 promoter. Thus, activated LSD1 hypomethylates H3K9 at the MMP-9 promoter and this frees up that lysine 9 for acetylation. Increased Ac-H3K9 facilitates the recruitment of p65, resulting in MMP-9 activation and mitochondrial damage. Thus, the regulation of LSD1 by molecular or pharmacological means has the potential to retard the development of diabetic retinopathy.
PMID
Related Publications

Epigenetic changes in mitochondrial superoxide dismutase in the retina and the development of diabetic retinopathy.

Epigenetic modification of Sod2 in the development of diabetic retinopathy and in the metabolic memory: role of histone methylation.

Sirt1, a negative regulator of matrix metalloproteinase-9 in diabetic retinopathy.

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

Crosstalk Between Histone and DNA Methylation in Regulation of Retinal Matrix Metalloproteinase-9 in Diabetes.

Authors

Mayor MeshTerms

Epigenesis, Genetic

Keywords
Journal Title diabetes
Publication Year Start




PMID- 23423566
OWN - NLM
STAT- MEDLINE
DCOM- 20130909
LR  - 20161019
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Linking)
VI  - 62
IP  - 7
DP  - 2013 Jul
TI  - Regulation of matrix metalloproteinase-9 by epigenetic modifications and the
      development of diabetic retinopathy.
PG  - 2559-68
LID - 10.2337/db12-1141 [doi]
AB  - Diabetes activates retinal matrix metalloproteinase-9 (MMP-9), and MMP-9 damages 
      the mitochondria and augments capillary cell apoptosis. Our aim is to elucidate
      the mechanism responsible for MMP-9 activation. Histone modifications and
      recruitment of the nuclear transcriptional factor-kappaB (p65 subunit) at the
      MMP-9 promoter and the activity of lysine-specific demethylase 1 (LSD1) were
      measured in the retina from streptozotocin-induced diabetic rats. The role of
      LSD1 in MMP-9 activation was investigated in isolated retinal endothelial cells
      transfected with LSD1 small interfering RNA (siRNA). The results were confirmed
      in the retina from human donors with diabetic retinopathy. Diabetes decreased
      histone H3 dimethyl lysine 9 (H3K9me2) and increased acetyl H3K9 (Ac-H3K9) and
      p65 at the retinal MMP-9 promoter. LSD1 enzyme activity and its transcripts were 
      elevated. LSD1 siRNA ameliorated the glucose-induced decrease in H3K9me2 and
      increase in p65 at the MMP-9 promoter, and prevented MMP-9 activation,
      mitochondrial damage, and cell apoptosis. Human donors with diabetic retinopathy 
      had similar epigenetic changes at the MMP-9 promoter. Thus, activated LSD1
      hypomethylates H3K9 at the MMP-9 promoter and this frees up that lysine 9 for
      acetylation. Increased Ac-H3K9 facilitates the recruitment of p65, resulting in
      MMP-9 activation and mitochondrial damage. Thus, the regulation of LSD1 by
      molecular or pharmacological means has the potential to retard the development of
      diabetic retinopathy.
FAU - Zhong, Qing
AU  - Zhong Q
AD  - Kresge Eye Institute, Wayne State University, Detroit, Michigan, USA.
FAU - Kowluru, Renu A
AU  - Kowluru RA
LA  - eng
GR  - P30 DK020572/DK/NIDDK NIH HHS/United States
GR  - R01 EY014370/EY/NEI NIH HHS/United States
GR  - R01 EY017313/EY/NEI NIH HHS/United States
GR  - R01 EY022230/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130219
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Histones)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 1.14.11.- (Histone Demethylases)
RN  - EC 1.14.11.- (LSD1 protein, rat)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - IY9XDZ35W2 (Glucose)
SB  - AIM
SB  - IM
MH  - Adult
MH  - Aged
MH  - Animals
MH  - Apoptosis/drug effects/physiology
MH  - Diabetes Mellitus, Experimental/genetics/*metabolism
MH  - Diabetic Retinopathy/genetics/*metabolism
MH  - Endothelial Cells/drug effects/metabolism
MH  - *Epigenesis, Genetic
MH  - Glucose/pharmacology
MH  - Histone Demethylases/genetics/metabolism
MH  - Histones/genetics/metabolism
MH  - Humans
MH  - Male
MH  - Matrix Metalloproteinase 9/genetics/*metabolism
MH  - Middle Aged
MH  - Promoter Regions, Genetic
MH  - Rats
MH  - Rats, Wistar
MH  - Reactive Oxygen Species/metabolism
MH  - Retina/drug effects/*enzymology
PMC - PMC3712057
OID - NLM: PMC3712057
EDAT- 2013/02/21 06:00
MHDA- 2013/09/10 06:00
CRDT- 2013/02/21 06:00
PHST- 2013/02/21 06:00 [entrez]
PHST- 2013/02/21 06:00 [pubmed]
PHST- 2013/09/10 06:00 [medline]
AID - db12-1141 [pii]
AID - 10.2337/db12-1141 [doi]
PST - ppublish
SO  - Diabetes. 2013 Jul;62(7):2559-68. doi: 10.2337/db12-1141. Epub 2013 Feb 19.