PMID- 19021146
OWN - NLM
STAT- MEDLINE
DCOM- 20090213
LR  - 20211020
IS  - 1097-4644 (Electronic)
IS  - 0730-2312 (Print)
IS  - 0730-2312 (Linking)
VI  - 106
IP  - 1
DP  - 2009 Jan 1
TI  - Nitrotyrosinylation, remodeling and endothelial-myocyte uncoupling in iNOS, 
      cystathionine beta synthase (CBS) knockouts and iNOS/CBS double knockout mice.
PG  - 119-26
LID - 10.1002/jcb.21982 [doi]
AB  - Increased levels of homocysteine (Hcy), recognized as hyperhomocysteinemia 
      (HHcy), were associated with cardiovascular diseases. There was controversy 
      regarding the detrimental versus cardio protective role of inducible nitric oxide 
      synthase (iNOS) in ischemic heart disease. The aim of this study was to test the 
      hypothesis that the Hcy generated nitrotyrosine by inducing the endothelial 
      nitric oxide synthase, causing endothelial-myocyte (E-M) coupling. To 
      differentiate the role of iNOS versus constitutive nitric oxide synthase (eNOS 
      and nNOS) in Hcy-mediated nitrotyrosine generation and matrix remodeling in 
      cardiac dysfunction, left ventricular (LV) tissue was analyzed from cystathionine 
      beta synthase (CBS) heterozygote knockout, iNOS homozygote knockout, 
      CBS-/+/iNOS-/- double knockout, and wild-type (WT) mice. The levels of 
      nitrotyrosine, MMP-2 and -9 (zymographic analysis), and fibrosis (by trichrome 
      stain) were measured. The endothelial-myocyte function was determined in cardiac 
      rings. In CBS-/+ mice, homocysteine was elevated and in iNOS-/- mice, nitric 
      oxide was significantly reduced. The nitrotyrosine and matrix metalloproteinase-9 
      (MMP-9) levels were elevated in double knockout and CBS-/+ as compared to WT 
      mice. Although MMP-2 levels were similar in CBS-/+, iNOS-/-, and CBS-/+/iNOS-/-, 
      the levels were three- to fourfold higher than WT. The levels of collagen were 
      similar in CBS-/+ and iNOS-/-, but they were threefold higher than WT. 
      Interesting, the levels of collagen increased sixfold in double knockouts, 
      compared to WT, suggesting synergism between high Hcy and lack of iNOS. Left 
      ventricular hypertrophy was exaggerated in the iNOS-/- and double knockout, and 
      mildly increased in the CBS-/+, compared to WT mice. The endothelial-dependent 
      relaxation was attenuated to the same extent in the CBS-/+ and iNOS-/-, compared 
      to WT, but it was robustly blunted in double knockouts. The results concluded 
      that homocysteine generated nitrotyrosine in the vicinity of endothelium, caused 
      MMP activation and endothelium-myocyte uncoupling. The generation of 
      nitrotyrosine was independent of iNOS.
CI  - 2008 Wiley-Liss, Inc.
FAU - Kundu, Soumi
AU  - Kundu S
AD  - Department of Physiology & Biophysics, University of Louisville School of 
      Medicine, Louisville, Kentucky 40202, USA.
FAU - Kumar, Munish
AU  - Kumar M
FAU - Sen, Utpal
AU  - Sen U
FAU - Mishra, Paras K
AU  - Mishra PK
FAU - Tyagi, Neetu
AU  - Tyagi N
FAU - Metreveli, Naira
AU  - Metreveli N
FAU - Lominadze, David
AU  - Lominadze D
FAU - Rodriguez, Walter
AU  - Rodriguez W
FAU - Tyagi, Suresh C
AU  - Tyagi SC
LA  - eng
GR  - R01 HL074185/HL/NHLBI NIH HHS/United States
GR  - R01 HL080394-03/HL/NHLBI NIH HHS/United States
GR  - R01 HL080394/HL/NHLBI NIH HHS/United States
GR  - R01 HL074185-05/HL/NHLBI NIH HHS/United States
GR  - R01 HL071010/HL/NHLBI NIH HHS/United States
GR  - R01 NS051568/NS/NINDS NIH HHS/United States
GR  - R01 HL088012/HL/NHLBI NIH HHS/United States
GR  - HL-74185/HL/NHLBI NIH HHS/United States
GR  - R01 HL071010-06/HL/NHLBI NIH HHS/United States
GR  - R01 NS051568-02/NS/NINDS NIH HHS/United States
GR  - HL-88012/HL/NHLBI NIH HHS/United States
GR  - HL-71010/HL/NHLBI NIH HHS/United States
GR  - NS-51568/NS/NINDS NIH HHS/United States
GR  - R01 HL088012-02/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - J Cell Biochem
JT  - Journal of cellular biochemistry
JID - 8205768
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 3604-79-3 (3-nitrotyrosine)
RN  - 42HK56048U (Tyrosine)
RN  - 9007-34-5 (Collagen)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 3.4.24.24 (Matrix Metalloproteinase 2)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - EC 4.2.1.22 (Cystathionine beta-Synthase)
SB  - IM
MH  - Animals
MH  - Collagen/metabolism
MH  - Cystathionine beta-Synthase/*genetics/metabolism
MH  - Endothelium, Vascular/*metabolism
MH  - Genotype
MH  - Homocysteine/metabolism
MH  - Hypertrophy, Left Ventricular/genetics/metabolism
MH  - Matrix Metalloproteinase 2/metabolism
MH  - Matrix Metalloproteinase 9/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Muscle Cells/*metabolism
MH  - Nitric Oxide Synthase Type II/*genetics/metabolism
MH  - Phenotype
MH  - Tyrosine/*analogs & derivatives/metabolism
MH  - Ventricular Remodeling
PMC - PMC2668975
MID - NIHMS100674
EDAT- 2008/11/21 09:00
MHDA- 2009/02/14 09:00
PMCR- 2009/04/14
CRDT- 2008/11/21 09:00
PHST- 2008/11/21 09:00 [pubmed]
PHST- 2009/02/14 09:00 [medline]
PHST- 2008/11/21 09:00 [entrez]
PHST- 2009/04/14 00:00 [pmc-release]
AID - 10.1002/jcb.21982 [doi]
PST - ppublish
SO  - J Cell Biochem. 2009 Jan 1;106(1):119-26. doi: 10.1002/jcb.21982.