Expression of matrix metalloproteinase-9 in mononuclear cells of hyperhomocysteinaemic subjects.
Atherosclerotic plaque instability and rupture requires extracellular matrix modification, a complex process regulated by matrix metalloproteinases (MMPs). We hypothesized that homocysteine's atherogenic effects may involve MMP-mediated mechanisms. Our results showed the following: (i) Compared with healthy control subjects (n = 9), patients with hyperhomocysteinaemia (n = 9) had elevated mRNA levels of MMP-9 and tissue inhibitors of metalloproteinases-1 (TIMP-1) in freshly isolated peripheral blood mononuclear cells (PBMCs), which were positively correlated with homocysteine and negatively correlated with folate and vitamin B12 levels. (ii) Peripheral blood mononuclear cells obtained from these patients released markedly enhanced the amount of MMP-9 upon oxidized LDL (oxLDL) stimulation, whereas no such enhancing effect was seen in cells from healthy controls. (iii) During folic acid 6 weeks' treatment, normalization of homocysteine levels was accompanied by a significant reduction in mRNA levels of MMP-9 and TIMP-1 in PBMCs, as well as a marked reduction in oxLDL-stimulated release of MMP enzyme activity. These novel findings may suggest that homocysteine exerts its atherogenic effect in part by elevating levels and activity of MMPs, which in turn may enhance matrix degradation, potentially promoting atherogenesis and plaque instability. Moreover, our findings suggest that folic acid supplementation may down-regulate these inappropriate responses in these patients.
Holven
K B
KB
Research Institute for Internal Medicine, Rikshospitalet University Hospital, 0027 Oslo, Norway.
Halvorsen
B
B
Schulz
H
H
Aukrust
P
P
Ose
L
L
Nenseter
M S
MS
D005260:Female; D005492:Folic Acid / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood* / Q000188:drug therapy; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*
D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D005492:Folic Acid; D020780:Matrix Metalloproteinase 9