PMID- 16877562
OWN - NLM
STAT- MEDLINE
DCOM- 20070116
LR  - 20200930
IS  - 0363-6135 (Print)
IS  - 0363-6135 (Linking)
VI  - 291
IP  - 6
DP  - 2006 Dec
TI  - Homocysteine-mediated activation and mitochondrial translocation of calpain 
      regulates MMP-9 in MVEC.
PG  - H2825-35
AB  - Hyperhomocysteinemia (HHcy) is associated with atherosclerosis, stroke, and 
      dementia. Hcy causes extracellular matrix remodeling by the activation of matrix 
      metalloproteinase-9 (MMP-9), in part, by inducing redox signaling and modulating 
      the intracellular calcium dynamics. Calpains are the calcium-dependent cysteine 
      proteases that are implicated in mitochondrial damage via oxidative burst. 
      Mitochondrial abnormalities have been identified in HHcy. The mechanism of 
      Hcy-induced extracellular matrix remodeling by MMP-9 activation via mitochondrial 
      pathway is largely unknown. We report a novel role of calpains in 
      mitochondrial-mediated MMP-9 activation by Hcy in cultured rat heart 
      microvascular endothelial cells. Our observations suggested that calpain 
      regulates Hcy-induced MMP-9 expression and activity. We showed that Hcy activates 
      calpain-1, but not calpain-2, in a calcium-dependent manner. Interestingly, the 
      enhanced calpain activity was not mirrored by the decreased levels of its 
      endogenous inhibitor calpastatin. We presented evidence that Hcy induces the 
      translocation of active calpain from cytosol to mitochondria, leading to MMP-9 
      activation, in part, by causing intramitochondrial oxidative burst. Furthermore, 
      studies with pharmacological inhibitors of calpain (calpeptin and calpain-1 
      inhibitor), ERK (PD-98059) and the mitochondrial uncoupler FCCP suggested that 
      calpain and ERK-1/2 are the major events within the Hcy/MMP-9 signal axis and 
      that intramitochondrial oxidative stress regulates MMP-9 via ERK-1/2 signal 
      cascade. Taken together, these findings determine the novel role of mitochondrial 
      translocation of calpain-1 in MMP-9 activation during HHcy, in part, by 
      increasing mitochondrial oxidative stress.
FAU - Moshal, Karni S
AU  - Moshal KS
AD  - Dept. of Physiology and Biophysics, School of Medicine, University of Louisville, 
      Louisville, KY 40202, USA.
FAU - Singh, Mahavir
AU  - Singh M
FAU - Sen, Utpal
AU  - Sen U
FAU - Rosenberger, Dorothea Susanne E
AU  - Rosenberger DS
FAU - Henderson, Brooke
AU  - Henderson B
FAU - Tyagi, Neetu
AU  - Tyagi N
FAU - Zhang, Hong
AU  - Zhang H
FAU - Tyagi, Suresh C
AU  - Tyagi SC
LA  - eng
GR  - HL-71010/HL/NHLBI NIH HHS/United States
GR  - HL-74185/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20060728
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (Dipeptides)
RN  - 0 (Flavonoids)
RN  - 0 (Uncoupling Agents)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 18X9FR245W (calpeptin)
RN  - 370-86-5 (Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone)
RN  - 79079-11-1 (calpastatin)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 3.4.22.- (Calpain)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)
SB  - IM
MH  - Animals
MH  - Calcium-Binding Proteins/metabolism
MH  - Calpain/antagonists & inhibitors/*metabolism
MH  - Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone/pharmacology
MH  - Cells, Cultured
MH  - Coronary Vessels/metabolism/pathology
MH  - Cytosol/metabolism
MH  - Dipeptides/pharmacology
MH  - Endothelium, Vascular/*metabolism/pathology
MH  - Flavonoids/pharmacology
MH  - Gene Expression Regulation, Enzymologic/drug effects
MH  - Homocysteine/*physiology
MH  - Hyperhomocysteinemia/*metabolism
MH  - Matrix Metalloproteinase 9/genetics/*metabolism
MH  - Mitochondria/*metabolism
MH  - Mitogen-Activated Protein Kinase 3/metabolism
MH  - Oxidative Stress
MH  - Rats
MH  - Rats, Wistar
MH  - Uncoupling Agents/pharmacology
EDAT- 2006/08/01 09:00
MHDA- 2007/01/17 09:00
CRDT- 2006/08/01 09:00
PHST- 2006/08/01 09:00 [pubmed]
PHST- 2007/01/17 09:00 [medline]
PHST- 2006/08/01 09:00 [entrez]
AID - 00377.2006 [pii]
AID - 10.1152/ajpheart.00377.2006 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2006 Dec;291(6):H2825-35. doi: 
      10.1152/ajpheart.00377.2006. Epub 2006 Jul 28.