PMID- 17543638
OWN - NLM
STAT- MEDLINE
DCOM- 20070705
LR  - 20220223
IS  - 1558-3597 (Electronic)
IS  - 0735-1097 (Linking)
VI  - 49
IP  - 22
DP  - 2007 Jun 5
TI  - Homocysteine modulates the CD40/CD40L system.
PG  - 2182-90
AB  - OBJECTIVES: This study evaluated the impact of hyperhomocysteinemia (HHcy) on the 
      CD40/CD40 ligand (CD40L) dyad in vivo and in vitro. BACKGROUND: 
      Hyperhomocysteinemia is associated with an increased incidence of 
      atherothrombosis, although the molecular mechanisms of this association are 
      incompletely defined. The CD40L pair triggers inflammatory signals in cells of 
      the vascular wall, representing a major pathogenetic pathway of atherosclerosis. 
      METHODS: We used a commercially available enzyme-linked immunosorbent assay kit 
      to evaluate circulating levels of soluble (s) CD40L in 24 patients with HHcy and 
      24 healthy subjects. We also used real-time polymerase chain reaction and flow 
      cytometry to determine expression levels of CD40 and vascular cell adhesion 
      molecule (VCAM)-1 in human umbilical vein endothelial cells (HUVECs) and of CD40L 
      in human platelets. RESULTS: The sCD40L levels were significantly increased in 
      HHcy patients (median [interquartile range] 8.0 [0.7 to 10.5] ng/ml vs. 2.1 [1.9 
      to 2.3] ng/ml, p = 0.0001). Positive correlations were noted between log sCD40L 
      and log homocysteine (Hcy) (R = 0.68, p < 0.0001) or log sVCAM-1 (R = 0.41, p < 
      0.005). Homocysteine significantly stimulated CD40 mRNA expression in HUVECs (p = 
      0.033). Consistently, 24-h exposure to Hcy increased the percentage of 
      CD40-expressing cells (p = 0.00025). Homocysteine also significantly enhanced 
      CD40L expression in platelets (p = 0.025) to a comparable extent as that of 
      thrombin. Notably, Hcy increased VCAM-1 protein expression induced by CD40L in 
      HUVECs (p = 0.0046). CONCLUSIONS: The present results uncover a potential 
      molecular target of Hcy, namely the CD40/CD40L dyad. Collectively, they indicate 
      that upregulation of CD40/CD40L signaling may represent a link between HHcy and 
      an increased risk of cardiovascular disease.
FAU - Prontera, Cesaria
AU  - Prontera C
AD  - Department of Medicine, Gabriele d'Annunzio University Foundation, 
      Chieti-Pescara, Italy.
FAU - Martelli, Nicola
AU  - Martelli N
FAU - Evangelista, Virgilio
AU  - Evangelista V
FAU - D'Urbano, Etrusca
AU  - D'Urbano E
FAU - Manarini, Stefano
AU  - Manarini S
FAU - Recchiuti, Antonio
AU  - Recchiuti A
FAU - Dragani, Alfredo
AU  - Dragani A
FAU - Passeri, Cecilia
AU  - Passeri C
FAU - Davi, Giovanni
AU  - Davi G
FAU - Romano, Mario
AU  - Romano M
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070518
PL  - United States
TA  - J Am Coll Cardiol
JT  - Journal of the American College of Cardiology
JID - 8301365
RN  - 0 (CD40 Antigens)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 147205-72-9 (CD40 Ligand)
RN  - EC 1.5.1.20 (Methylenetetrahydrofolate Reductase (NADPH2))
SB  - IM
MH  - Adult
MH  - Blood Platelets/metabolism
MH  - CD40 Antigens/*blood/genetics/physiology
MH  - CD40 Ligand/*blood/genetics/physiology
MH  - Endothelial Cells/metabolism
MH  - Female
MH  - Homocysteine/blood/genetics/*physiology
MH  - Humans
MH  - Male
MH  - Methylenetetrahydrofolate Reductase (NADPH2)/blood/genetics
MH  - Middle Aged
MH  - Signal Transduction/physiology
MH  - Up-Regulation/physiology
EDAT- 2007/06/05 09:00
MHDA- 2007/07/06 09:00
CRDT- 2007/06/05 09:00
PHST- 2006/01/31 00:00 [received]
PHST- 2006/12/20 00:00 [revised]
PHST- 2007/02/09 00:00 [accepted]
PHST- 2007/06/05 09:00 [pubmed]
PHST- 2007/07/06 09:00 [medline]
PHST- 2007/06/05 09:00 [entrez]
AID - S0735-1097(07)00981-3 [pii]
AID - 10.1016/j.jacc.2007.02.044 [doi]
PST - ppublish
SO  - J Am Coll Cardiol. 2007 Jun 5;49(22):2182-90. doi: 10.1016/j.jacc.2007.02.044. 
      Epub 2007 May 18.