PMID- 18393909
OWN - NLM
STAT- MEDLINE
DCOM- 20080718
LR  - 20220316
IS  - 1570-1611 (Print)
IS  - 1570-1611 (Linking)
VI  - 6
IP  - 2
DP  - 2008 Apr
TI  - Mitochondrial MMP activation, dysfunction and arrhythmogenesis in 
      hyperhomocysteinemia.
PG  - 84-92
AB  - Chronic volume/pressure overload-induced heart failure augments oxidative stress 
      and activates matrix metalloproteinase which causes endocardial 
      endothelial-myocyte (EM) uncoupling eventually leading to decline in myocardial 
      systolic and diastolic function. The elevated levels of homocysteine (Hcy), 
      hyperhomocysteinemia (HHcy), are associated with decline in cardiac performance. 
      Hcy impairs the EM functions associated with the induction of ventricular 
      hypertrophy leading to cardiac stiffness and diastolic heart failure. Hcy-induced 
      neurological defects are mediated by the NMDA-R (N-methyl-D-aspartate (NMDA) 
      receptor) activation. NMDA-R is expressed in the heart. However, the role of 
      NMDA-R on cardiac function during HHcy is still in its infancy. The blockade of 
      NMDA-R attenuates NMDA-agonist-induced increase in the heart rate. Hcy increases 
      intracellular calcium and activates calpain and calpain-associated mitochondrial 
      (mt) abnormalities have been identified in HHcy. Mitochondrial permeabilization 
      and uncoupling in the pathological setting is fueled by redox stress and calcium 
      mishandling. Recently the role of cyclophilin D, a component of the mitochondrial 
      membrane permeability transition pore, has been identified in cardiac-ischemia. 
      Mechanisms underlying the potentiation between NMDA-R activation and 
      mitochondrial defects leading to cardiac dysfunction during HHcy remain to be 
      elucidated. This review addresses the mitochondrial mechanism by which Hcy 
      contributes to the decline in mechano-electrical function and arrhythmogenesis 
      via agonizing NMDA-R. The putative role of mitochondrial MMP activation, protease 
      stress and mitochondrial permeability transition in cardiac conduction during 
      HHcy is discussed. The review suggests that Hcy increases calcium overload and 
      oxidative stress in the mitochondria and amplifies the activation of mtMMP, 
      causing the opening of mitochondrial permeability transition pore leading to 
      mechano-electrical dysfunction.
FAU - Moshal, Karni S
AU  - Moshal KS
AD  - Department of Physiology and Biophysics, University of Louisville School of 
      Medicine, Louisville, KY 40202, USA.
FAU - Metreveli, Naira
AU  - Metreveli N
FAU - Frank, Iuliana
AU  - Frank I
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
GR  - HL-88012/HL/NHLBI NIH HHS/United States
GR  - NS-51568/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - United Arab Emirates
TA  - Curr Vasc Pharmacol
JT  - Current vascular pharmacology
JID - 101157208
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Arrhythmias, Cardiac/complications/*metabolism/physiopathology
MH  - Calcium/metabolism
MH  - Enzyme Activation
MH  - Extracellular Matrix/physiology
MH  - Heart Failure/complications/*metabolism/physiopathology
MH  - Homocysteine/physiology
MH  - Humans
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology/therapeutic use
MH  - Hyperhomocysteinemia/complications/*metabolism/physiopathology
MH  - Matrix Metalloproteinases/*metabolism
MH  - Mitochondria, Heart/enzymology/*physiology
MH  - Myocytes, Cardiac/physiology
MH  - Oxidative Stress
MH  - Receptors, N-Methyl-D-Aspartate/physiology
MH  - Signal Transduction
RF  - 74
EDAT- 2008/04/09 09:00
MHDA- 2008/07/19 09:00
CRDT- 2008/04/09 09:00
PHST- 2008/04/09 09:00 [pubmed]
PHST- 2008/07/19 09:00 [medline]
PHST- 2008/04/09 09:00 [entrez]
AID - 10.2174/157016108783955301 [doi]
PST - ppublish
SO  - Curr Vasc Pharmacol. 2008 Apr;6(2):84-92. doi: 10.2174/157016108783955301.