PMID- 21653942
OWN - NLM
STAT- MEDLINE
DCOM- 20111012
LR  - 20220311
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 118
IP  - 7
DP  - 2011 Aug 18
TI  - Hyperhomocysteinemia impairs endothelium-derived hyperpolarizing factor-mediated 
      vasorelaxation in transgenic cystathionine beta synthase-deficient mice.
PG  - 1998-2006
LID - 10.1182/blood-2011-01-333310 [doi]
AB  - Hyperhomocysteinemia (HHcy) is associated with endothelial dysfunction (ED), but 
      the mechanism is largely unknown. In this study, we investigated the role and 
      mechanism of HHcy-induced ED in microvasculature in our newly established mouse 
      model of severe HHcy (plasma total homocysteine, 169.5 muM). We found that severe 
      HHcy impaired nitric oxide (NO)- and endothelium-derived hyperpolarizing factor 
      (EDHF)-mediated, endothelium-dependent relaxations of small mesenteric arteries 
      (SMAs). Endothelium-independent and prostacyclin-mediated endothelium-dependent 
      relaxations were not changed. A nonselective Ca(2+)-activated potassium channel 
      (K(Ca)) inhibitor completely blocked EDHF-mediated relaxation. Selective blockers 
      for small-conductance K(Ca) (SK) or intermediate-conductance K(Ca) (IK) failed to 
      inhibit EDHF-mediated relaxation in HHcy mice. HHcy increased the levels of SK3 
      and IK1 protein, superoxide (O(2)(-)), and 3-nitrotyrosine in the endothelium of 
      SMAs. Preincubation with antioxidants and peroxynitrite (ONOO(-)) inhibitors 
      improved endothelium-dependent and EDHF-mediated relaxations and decreased 
      O(2)(-) production in SMAs from HHcy mice. Further, EDHF-mediated relaxation was 
      inhibited by ONOO(-) and prevented by catalase in the control mice. Finally, 
      L-homocysteine stimulated O(2)(-) production, which was reversed by antioxidants, 
      and increased SK/IK protein levels and tyrosine nitration in cultured human 
      cardiac microvascular endothelial cells. Our results suggest that HHcy impairs 
      EDHF relaxation in SMAs by inhibiting SK/IK activities via oxidation- and 
      tyrosine nitration-related mechanisms.
FAU - Cheng, Zhongjian
AU  - Cheng Z
AD  - Department of Pharmacology, Temple University School of Medicine, Philadelphia, 
      PA 19140, USA.
FAU - Jiang, Xiaohua
AU  - Jiang X
FAU - Kruger, Warren D
AU  - Kruger WD
FAU - Pratico, Domenico
AU  - Pratico D
FAU - Gupta, Sapna
AU  - Gupta S
FAU - Mallilankaraman, Karthik
AU  - Mallilankaraman K
FAU - Madesh, Muniswamy
AU  - Madesh M
FAU - Schafer, Andrew I
AU  - Schafer AI
FAU - Durante, William
AU  - Durante W
FAU - Yang, Xiaofeng
AU  - Yang X
FAU - Wang, Hong
AU  - Wang H
LA  - eng
GR  - HL82774/HL/NHLBI NIH HHS/United States
GR  - R01 HL077288/HL/NHLBI NIH HHS/United States
GR  - HL74966/HL/NHLBI NIH HHS/United States
GR  - R01 HL074966/HL/NHLBI NIH HHS/United States
GR  - HL77288/HL/NHLBI NIH HHS/United States
GR  - HL67033/HL/NHLBI NIH HHS/United States
GR  - R01 HL082774/HL/NHLBI NIH HHS/United States
GR  - R29 HL057299/HL/NHLBI NIH HHS/United States
GR  - HL57299/HL/NHLBI NIH HHS/United States
GR  - R01 HL094451/HL/NHLBI NIH HHS/United States
GR  - HL94451/HL/NHLBI NIH HHS/United States
GR  - R01 HL057299/HL/NHLBI NIH HHS/United States
GR  - R01 HL086699/HL/NHLBI NIH HHS/United States
GR  - R01 HL067033/HL/NHLBI NIH HHS/United States
GR  - HL86699/HL/NHLBI NIH HHS/United States
GR  - SLORR27327/PHS HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20110608
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Biological Factors)
RN  - 0 (Nitrogen Oxides)
RN  - 0 (endothelium-dependent hyperpolarization factor)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - EC 4.2.1.22 (Cystathionine beta-Synthase)
SB  - IM
CIN - Blood. 2011 Aug 18;118(7):1717-9. PMID: 21852445
MH  - Animals
MH  - Biological Factors/*metabolism
MH  - Cardiovascular Diseases/etiology
MH  - Cell Line
MH  - Cystathionine beta-Synthase/*genetics
MH  - Gene Deletion
MH  - Homocysteine/blood
MH  - Humans
MH  - Hyperhomocysteinemia/genetics/metabolism/*physiopathology
MH  - Mesenteric Arteries/metabolism/*physiopathology
MH  - Mice
MH  - Mice, Transgenic
MH  - Nitrogen Oxides/metabolism
MH  - *Vasodilation
PMC - PMC3158725
EDAT- 2011/06/10 06:00
MHDA- 2011/10/13 06:00
PMCR- 2012/08/18
CRDT- 2011/06/10 06:00
PHST- 2011/06/10 06:00 [entrez]
PHST- 2011/06/10 06:00 [pubmed]
PHST- 2011/10/13 06:00 [medline]
PHST- 2012/08/18 00:00 [pmc-release]
AID - S0006-4971(20)41115-2 [pii]
AID - 2011/333310 [pii]
AID - 10.1182/blood-2011-01-333310 [doi]
PST - ppublish
SO  - Blood. 2011 Aug 18;118(7):1998-2006. doi: 10.1182/blood-2011-01-333310. Epub 2011 
      Jun 8.