PMID- 17200441
OWN - NLM
STAT- MEDLINE
DCOM- 20070205
LR  - 20131121
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Linking)
VI  - 115
IP  - 2
DP  - 2007 Jan 16
TI  - Hyperhomocysteinemia alters cardiac substrate metabolism by impairing nitric 
      oxide bioavailability through oxidative stress.
PG  - 255-62
AB  - BACKGROUND: Hyperhomocysteinemia (HHcy) has been considered a vascular disease 
      associated with increased levels of oxidative stress that results in scavenging 
      of NO. However, little is known of the impact of HHcy on cardiac function and 
      especially myocardial metabolism. METHODS AND RESULTS: L-Homocysteine was 
      intravenously infused into conscious dogs, and the dogs were fed methionine to 
      increase plasma homocysteine to 10 micromol/L for acute and 24 micromol/L for 
      chronic HHcy. There was no significant change in hemodynamics with HHcy. 
      Veratrine-induced, NO-dependent, coronary vasodilation (Bezold-Jarisch reflex) 
      was reduced by 32% but was restored by simultaneous intravenous infusion of 
      ascorbic acid or apocynin. Acute and chronic HHcy significantly increased uptake 
      of glucose and lactate and decreased uptake of free fatty acid by the heart. HHcy 
      significantly decreased bradykinin- or carbachol-induced reduction of myocardial 
      oxygen consumption in vitro, and this effect was completely restored by 
      coincubation with ascorbic acid, Tempol, or apocynin. Western blot analysis 
      indicated an increase in Nox2 (82%) and a reduction in endothelial nitric oxide 
      synthase (39%), phospho-endothelial nitric oxide synthase (39%), and superoxide 
      dismutase-1 (45%). Microarray analysis of gene expression in heart tissue from 
      chronic HHcy indicated a switch in cardiac phenotype to enzymes that metabolize 
      glucose. CONCLUSIONS: HHcy directly modulates substrate use by the heart 
      independent of changes in hemodynamics or ventricular function by reducing NO 
      bioavailability through the generation of superoxide. The progression of cardiac 
      or coronary heart disease associated with HHcy should be evaluated in light of 
      the impact of alterations in the regulation of cardiac metabolism and substrate 
      use.
FAU - Suematsu, Nobuhiro
AU  - Suematsu N
AD  - Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
FAU - Ojaimi, Caroline
AU  - Ojaimi C
FAU - Kinugawa, Shintaro
AU  - Kinugawa S
FAU - Wang, Zipping
AU  - Wang Z
FAU - Xu, Xiaobin
AU  - Xu X
FAU - Koller, Akos
AU  - Koller A
FAU - Recchia, Fabio A
AU  - Recchia FA
FAU - Hintze, Thomas H
AU  - Hintze TH
LA  - eng
GR  - HL-63129/HL/NHLBI NIH HHS/United States
GR  - P01-HL-43023/HL/NHLBI NIH HHS/United States
GR  - P01-HL-74237/HL/NHLBI NIH HHS/United States
GR  - R01-HL-50142/HL/NHLBI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20070102
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 31C4KY9ESH (Nitric Oxide)
SB  - IM
MH  - Animals
MH  - Biological Availability
MH  - Blood Pressure/drug effects/physiology
MH  - Dogs
MH  - Heart Rate/drug effects/physiology
MH  - Homocysteine/metabolism/pharmacology
MH  - Hyperhomocysteinemia/*blood
MH  - Male
MH  - Nitric Oxide/*blood
MH  - Oxidative Stress/drug effects/*physiology
MH  - Substrate Specificity/drug effects/physiology
EDAT- 2007/01/04 09:00
MHDA- 2007/02/06 09:00
CRDT- 2007/01/04 09:00
PHST- 2007/01/04 09:00 [pubmed]
PHST- 2007/02/06 09:00 [medline]
PHST- 2007/01/04 09:00 [entrez]
AID - CIRCULATIONAHA.106.652693 [pii]
AID - 10.1161/CIRCULATIONAHA.106.652693 [doi]
PST - ppublish
SO  - Circulation. 2007 Jan 16;115(2):255-62. doi: 10.1161/CIRCULATIONAHA.106.652693. 
      Epub 2007 Jan 2.