PMID- 21760969
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20111110
LR  - 20211020
IS  - 1944-8171 (Electronic)
IS  - 1944-8171 (Linking)
VI  - 3
IP  - 2
DP  - 2011
TI  - Synergism between arrhythmia and hyperhomo-cysteinemia in structural heart 
      disease.
PG  - 107-19
AB  - Elevated levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy) is 
      associated with cardiac arrhythmia and sudden cardiac death (SCD). Hcy increases 
      iNOS, activates matrix metalloproteinase (MMP), disrupts connexin-43 and 
      increases collagen/elastin ratio. The disruption of connexin-43 and accumulation 
      of collagen (fibrosis) interupt cardiac conduction and attenuate NO transport 
      from endothelium to myocyte (E-M) causing E-M uncoupling. We hypothesize that Hcy 
      increases mtNOS, metalloproteinase activity, disrupts connexin-43, exacerbates 
      endothelial-myocyte uncoupling, and induces cardiac failure by activating NMDA-R1 
      in structural heart disease. Chronic volume overload heart failure was created by 
      aorta-venacava (AV) fistula. HHcy was induced by adminstrering Hcy in drinking 
      water. NMDA-R1 was blocked by dizocilpine (MK-801). EKG and M-mode 
      Echocardiography was performed. The E-M coupling was determined in cardiac rings. 
      LV mitochondria was isolated. Levels of NMDA-R1, peroxiredoxin, NOX4, and mtNOS 
      were measured. The degradation of connexin-43, collagen and elastin was measured 
      by Western blot analysis. Mouse cardiac endothelial cells were cultured with or 
      without Hcy or MK-801. The results suggest systolic and diastolic heart failure 
      in HHcy and AVF mice. The levels of connexin, collagen degradation and MMP-9 were 
      increased. The elastin was decreased in HHcy and AVF hearts. The mitochondrial 
      NOX4 increased and peroxiredoxin was decreased. The mtNOS activity was 
      synergistically increased in HHcy, AVF and HHcy+AVF hearts. The cardiac 
      contraction and endothelial dependent relaxation was attenutated in HHcy and AVF 
      hearts. Interestingly, the treatment with MK-801 mitigated the contractile 
      dysfunction. These studies delineated the mechanism of Hcy-dependent 
      endothelial-myocyte uncoupling in cardiac arrhythmia and failure, and have 
      therapeutic ramifications for sudden cardiac death.
FAU - Givvimani, Srikanth
AU  - Givvimani S
AD  - Department of Physiology and Biophysics, University of Louisville School of 
      Medicine Louisville, Kentucky.
FAU - Qipshidze, Natia
AU  - Qipshidze N
FAU - Tyagi, Neetu
AU  - Tyagi N
FAU - Mishra, Paras K
AU  - Mishra PK
FAU - Sen, Utpal
AU  - Sen U
FAU - Tyagi, Suresh C
AU  - Tyagi SC
LA  - eng
GR  - R01 HL071010/HL/NHLBI NIH HHS/United States
GR  - R01 HL074185/HL/NHLBI NIH HHS/United States
GR  - R01 HL088012/HL/NHLBI NIH HHS/United States
GR  - R01 HL108621/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20110529
PL  - United States
TA  - Int J Physiol Pathophysiol Pharmacol
JT  - International journal of physiology, pathophysiology and pharmacology
JID - 101521074
PMC - PMC3134005
OTO - NOTNLM
OT  - A-V fistula
OT  - MMP-9
OT  - NO
OT  - NOX4
OT  - PVC
OT  - calpain
OT  - connexin
OT  - endothelial myocyte coupling
OT  - heart failure
OT  - mitochondria
OT  - peroxiredoxin
EDAT- 2011/07/16 06:00
MHDA- 2011/07/16 06:01
PMCR- 2011/05/29
CRDT- 2011/07/16 06:00
PHST- 2011/05/05 00:00 [received]
PHST- 2011/05/23 00:00 [accepted]
PHST- 2011/07/16 06:00 [entrez]
PHST- 2011/07/16 06:00 [pubmed]
PHST- 2011/07/16 06:01 [medline]
PHST- 2011/05/29 00:00 [pmc-release]
PST - ppublish
SO  - Int J Physiol Pathophysiol Pharmacol. 2011;3(2):107-19. Epub 2011 May 29.