PMID- 21169404
OWN - NLM
STAT- MEDLINE
DCOM- 20110526
LR  - 20200930
IS  - 1522-1539 (Electronic)
IS  - 0363-6135 (Linking)
VI  - 300
IP  - 3
DP  - 2011 Mar
TI  - Mthfr deficiency induces endothelial progenitor cell senescence via uncoupling of 
      eNOS and downregulation of SIRT1.
PG  - H745-53
LID - 10.1152/ajpheart.00321.2010 [doi]
AB  - Hyperhomocysteinemia (HHcy) has been shown to induce endothelial dysfunction in 
      part as a result of enhanced oxidative stress. Function and survival of 
      endothelial progenitor cells (EPCs, defined as sca1(+) c-kit(+) flk-1(+) bone 
      marrow-derived cells), which significantly contribute to neovascularization and 
      endothelial regeneration, depend on controlled production of reactive oxygen 
      species (ROS). Mice heterozygous for the gene deletion of 
      methylenetetrahydrofolate reductase (Mthfr(+/-)) have a 1.5- to 2-fold elevation 
      in plasma homocysteine. This mild HHcy significantly reduced the number of 
      circulating EPCs as well as their differentiation. Mthfr deficiency was also 
      associated with increased ROS production and reduced nitric oxide (NO) generation 
      in Mthfr(+/-) EPCs. Treatment of EPCs with sepiapterin, a precursor of 
      tetrahydrobiopterin (BH(4)), a cofactor of endothelial nitric oxide synthase 
      (eNOS), significantly reduced ROS and improved NO production. mRNA and protein 
      expression of eNOS and the relative amount of eNOS dimer compared with monomer 
      were decreased by Mthfr deficiency. Impaired differentiation of EPCs induced by 
      Mthfr deficiency correlated with increased senescence, decreased telomere length, 
      and reduced expression of SIRT1. Addition of sepiapterin maintained cell 
      senescence and SIRT1 expression at levels comparable to the wild type. Taken 
      together, these results demonstrate that Mthfr deficiency impairs EPC formation 
      and increases EPC senescence by eNOS uncoupling and downregulation of SIRT1.
FAU - Lemarie, Catherine A
AU  - Lemarie CA
AD  - Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General 
      Hospital, McGill University, Montreal, Quebec, Canada.
FAU - Shbat, Layla
AU  - Shbat L
FAU - Marchesi, Chiara
AU  - Marchesi C
FAU - Angulo, Orlando J
AU  - Angulo OJ
FAU - Deschenes, Marie-Eve
AU  - Deschenes ME
FAU - Blostein, Mark D
AU  - Blostein MD
FAU - Paradis, Pierre
AU  - Paradis P
FAU - Schiffrin, Ernesto L
AU  - Schiffrin EL
LA  - eng
GR  - 37917/Canadian Institutes of Health Research/Canada
GR  - 82790/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101217
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Pterins)
RN  - 0 (Reactive Oxygen Species)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - CJQ26KO7HP (sepiapterin)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 1.5.1.20 (Methylenetetrahydrofolate Reductase (NADPH2))
RN  - EC 3.5.1.- (Sirt1 protein, mouse)
RN  - EC 3.5.1.- (Sirtuin 1)
RN  - Methylenetetrahydrofolate reductase deficiency
SB  - IM
MH  - Animals
MH  - Cell Differentiation/genetics
MH  - Cellular Senescence/*genetics
MH  - Down-Regulation
MH  - Endothelial Cells/*enzymology
MH  - Female
MH  - Homocystinuria/genetics
MH  - Hyperhomocysteinemia/drug therapy/enzymology/genetics
MH  - Methylenetetrahydrofolate Reductase (NADPH2)/deficiency/genetics
MH  - Mice
MH  - Muscle Spasticity/genetics
MH  - Nitric Oxide/metabolism
MH  - Nitric Oxide Synthase Type III/*metabolism
MH  - Oxidative Stress/drug effects/genetics
MH  - Psychotic Disorders/genetics
MH  - Pterins/pharmacology
MH  - Reactive Oxygen Species
MH  - Sirtuin 1/*metabolism
MH  - Stem Cells/*enzymology
MH  - Telomere/metabolism
EDAT- 2010/12/21 06:00
MHDA- 2011/05/27 06:00
CRDT- 2010/12/21 06:00
PHST- 2010/12/21 06:00 [entrez]
PHST- 2010/12/21 06:00 [pubmed]
PHST- 2011/05/27 06:00 [medline]
AID - ajpheart.00321.2010 [pii]
AID - 10.1152/ajpheart.00321.2010 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2011 Mar;300(3):H745-53. doi: 
      10.1152/ajpheart.00321.2010. Epub 2010 Dec 17.