PMID- 25802182
OWN - NLM
STAT- MEDLINE
DCOM- 20160302
LR  - 20181113
IS  - 1438-2199 (Electronic)
IS  - 0939-4451 (Print)
IS  - 0939-4451 (Linking)
VI  - 47
IP  - 7
DP  - 2015 Jul
TI  - Homocysteine thiolactone and N-homocysteinylated protein induce pro-atherogenic 
      changes in gene expression in human vascular endothelial cells.
PG  - 1319-39
LID - 10.1007/s00726-015-1956-7 [doi]
AB  - Genetic or nutritional deficiencies in homocysteine (Hcy) metabolism lead to 
      hyperhomocysteinemia (HHcy) and cause endothelial dysfunction, a hallmark of 
      atherosclerosis. In addition to Hcy, related metabolites accumulate in HHcy but 
      their role in endothelial dysfunction is unknown. Here, we examine how 
      Hcy-thiolactone, N-Hcy-protein, and Hcy affect gene expression and molecular 
      pathways in human umbilical vein endothelial cells. We used microarray 
      technology, real-time quantitative polymerase chain reaction, and bioinformatic 
      analysis with PANTHER, DAVID, and Ingenuity Pathway Analysis (IPA) resources. We 
      identified 47, 113, and 30 mRNAs regulated by N-Hcy-protein, Hcy-thiolactone, and 
      Hcy, respectively, and found that each metabolite induced a unique pattern of 
      gene expression. Top molecular pathways affected by Hcy-thiolactone were 
      chromatin organization, one-carbon metabolism, and lipid-related processes 
      [-log(P value) = 20-31]. Top pathways affected by N-Hcy-protein and Hcy were 
      blood coagulation, sulfur amino acid metabolism, and lipid metabolism [-log(P 
      value)] = 4-11; also affected by Hcy-thiolactone, [-log(P value) = 8-14]. Top 
      disease related to Hcy-thiolactone, N-Hcy-protein, and Hcy was 'atherosclerosis, 
      coronary heart disease' [-log(P value) = 9-16]. Top-scored biological networks 
      affected by Hcy-thiolactone (score = 34-40) were cardiovascular disease and 
      function; those affected by N-Hcy-protein (score = 24-35) were 'small molecule 
      biochemistry, neurological disease,' and 'cardiovascular system development and 
      function'; and those affected by Hcy (score = 25-37) were 'amino acid metabolism, 
      lipid metabolism,' 'cellular movement, and cardiovascular and nervous system 
      development and function.' These results indicate that each Hcy metabolite 
      uniquely modulates gene expression in pathways important for vascular homeostasis 
      and identify new genes and pathways that are linked to HHcy-induced endothelial 
      dysfunction and vascular disease.
FAU - Gurda, Dorota
AU  - Gurda D
AD  - Institute of Bioorganic Chemistry, Poznan, Poland.
FAU - Handschuh, Luiza
AU  - Handschuh L
FAU - Kotkowiak, Weronika
AU  - Kotkowiak W
FAU - Jakubowski, Hieronim
AU  - Jakubowski H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150324
PL  - Austria
TA  - Amino Acids
JT  - Amino acids
JID - 9200312
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - D5H88XF24X (homocysteine thiolactone)
SB  - IM
MH  - Atherosclerosis/metabolism
MH  - Cells, Cultured
MH  - Homocysteine/*analogs & derivatives/pharmacology/physiology
MH  - Human Umbilical Vein Endothelial Cells/*metabolism
MH  - Humans
MH  - Hyperhomocysteinemia/metabolism
MH  - Metabolic Networks and Pathways
MH  - Transcriptional Activation
MH  - *Transcriptome
PMC - PMC4458266
EDAT- 2015/03/25 06:00
MHDA- 2016/03/05 06:00
PMCR- 2015/03/24
CRDT- 2015/03/25 06:00
PHST- 2015/01/28 00:00 [received]
PHST- 2015/03/04 00:00 [accepted]
PHST- 2015/03/25 06:00 [entrez]
PHST- 2015/03/25 06:00 [pubmed]
PHST- 2016/03/05 06:00 [medline]
PHST- 2015/03/24 00:00 [pmc-release]
AID - 1956 [pii]
AID - 10.1007/s00726-015-1956-7 [doi]
PST - ppublish
SO  - Amino Acids. 2015 Jul;47(7):1319-39. doi: 10.1007/s00726-015-1956-7. Epub 2015 
      Mar 24.