PMID- 22227328
OWN - NLM
STAT- MEDLINE
DCOM- 20120709
LR  - 20211021
IS  - 1095-8584 (Electronic)
IS  - 0022-2828 (Print)
IS  - 0022-2828 (Linking)
VI  - 52
IP  - 3
DP  - 2012 Mar
TI  - Homocysteine induces cardiomyocyte dysfunction and apoptosis through p38 
      MAPK-mediated increase in oxidant stress.
PG  - 753-60
LID - 10.1016/j.yjmcc.2011.12.009 [doi]
AB  - Elevated plasma homocysteine (Hcy) is a risk factor for cardiovascular disease. 
      While Hcy has been shown to promote endothelial dysfunction by decreasing the 
      bioavailability of nitric oxide and increasing oxidative stress in the 
      vasculature, the effects of Hcy on cardiomyocytes remain less understood. In this 
      study we explored the effects of hyperhomocysteinemia (HHcy) on myocardial 
      function ex vivo and examined the direct effects of Hcy on cardiomyocyte function 
      and survival in vitro. Studies with isolated hearts from wild type and HHcy mice 
      (heterozygous cystathionine-beta synthase deficient mice) demonstrated that HHcy 
      mouse hearts had more severely impaired cardiac relaxation and contractile 
      function and increased cell death following ischemia reperfusion (I/R). In 
      isolated cultured adult rat ventricular myocytes, exposure to Hcy for 24 h 
      impaired cardiomyocyte contractility in a concentration-dependent manner, and 
      promoted apoptosis as revealed by terminal dUTP nick-end labeling and cleaved 
      caspase-3 immunoblotting. These effects were associated with activation of p38 
      MAPK, decreased expression of thioredoxin (TRX) protein, and increased production 
      of reactive oxygen species (ROS). Inhibition of p38 MAPK by the selective 
      inhibitor SB203580 (5 muM) prevented all of these Hcy-induced changes. 
      Furthermore, adenovirus-mediated overexpression of TRX in cardiomyocytes 
      significantly attenuated Hcy-induced ROS generation, apoptosis, and impairment of 
      myocyte contractility. Thus, Hcy may increase the risk for CVD not only by 
      causing endothelial dysfunction, but also by directly exerting detrimental 
      effects on cardiomyocytes.
CI  - Copyright (c) 2011 Elsevier Ltd. All rights reserved.
FAU - Wang, Xu
AU  - Wang X
AD  - Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, 
      Boston, MA 02115, USA.
FAU - Cui, Lei
AU  - Cui L
FAU - Joseph, Jacob
AU  - Joseph J
FAU - Jiang, Bingbing
AU  - Jiang B
FAU - Pimental, David
AU  - Pimental D
FAU - Handy, Diane E
AU  - Handy DE
FAU - Liao, Ronglih
AU  - Liao R
FAU - Loscalzo, Joseph
AU  - Loscalzo J
LA  - eng
GR  - U01 HL108630/HL/NHLBI NIH HHS/United States
GR  - U54 HL070819/HL/NHLBI NIH HHS/United States
GR  - R01 HL061795/HL/NHLBI NIH HHS/United States
GR  - HL070819/HL/NHLBI NIH HHS/United States
GR  - P50 HL107192-01/HL/NHLBI NIH HHS/United States
GR  - HL061795/HL/NHLBI NIH HHS/United States
GR  - U54 HL070819-07/HL/NHLBI NIH HHS/United States
GR  - P01 HL048743-18/HL/NHLBI NIH HHS/United States
GR  - P01 HL048743/HL/NHLBI NIH HHS/United States
GR  - HL048743/HL/NHLBI NIH HHS/United States
GR  - HL108630/HL/NHLBI NIH HHS/United States
GR  - U01 HL108630-01/HL/NHLBI NIH HHS/United States
GR  - R37 HL061795/HL/NHLBI NIH HHS/United States
GR  - R21 HL089734/HL/NHLBI NIH HHS/United States
GR  - R37 HL061795-14/HL/NHLBI NIH HHS/United States
GR  - HL107192/HL/NHLBI NIH HHS/United States
GR  - HL089734/HL/NHLBI NIH HHS/United States
GR  - P50 HL107192/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20111229
PL  - England
TA  - J Mol Cell Cardiol
JT  - Journal of molecular and cellular cardiology
JID - 0262322
RN  - 0 (Reactive Oxygen Species)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 52500-60-4 (Thioredoxins)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Enzyme Activation/drug effects
MH  - Gene Expression Regulation/drug effects
MH  - Homocysteine/blood/*pharmacology
MH  - Hyperhomocysteinemia/metabolism/physiopathology
MH  - In Vitro Techniques
MH  - MAP Kinase Signaling System/drug effects
MH  - Male
MH  - Mice
MH  - Myocardial Contraction/drug effects
MH  - Myocytes, Cardiac/*drug effects/*metabolism
MH  - *Oxidative Stress
MH  - Rats
MH  - Rats, Wistar
MH  - Reactive Oxygen Species/metabolism
MH  - Thioredoxins/genetics/metabolism
MH  - p38 Mitogen-Activated Protein Kinases/*metabolism
PMC - PMC3294144
MID - NIHMS347122
COIS- CONFLICTS OF INTEREST None.
EDAT- 2012/01/10 06:00
MHDA- 2012/07/10 06:00
PMCR- 2013/03/01
CRDT- 2012/01/10 06:00
PHST- 2011/10/14 00:00 [received]
PHST- 2011/12/13 00:00 [revised]
PHST- 2011/12/20 00:00 [accepted]
PHST- 2012/01/10 06:00 [entrez]
PHST- 2012/01/10 06:00 [pubmed]
PHST- 2012/07/10 06:00 [medline]
PHST- 2013/03/01 00:00 [pmc-release]
AID - S0022-2828(11)00516-5 [pii]
AID - 10.1016/j.yjmcc.2011.12.009 [doi]
PST - ppublish
SO  - J Mol Cell Cardiol. 2012 Mar;52(3):753-60. doi: 10.1016/j.yjmcc.2011.12.009. Epub 
      2011 Dec 29.