Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis.
Plasma homocysteine levels are elevated in 20-30% of all patients with premature atherosclerosis. Although elevated homocysteine levels have been recognized as an independent risk factor for myocardial infarction and stroke, the mechanism by which these elevated levels cause atherosclerosis is unknown. To understand the role of homocysteine in the pathogenesis of atherosclerosis, we examined the effect of homocysteine on the growth of both vascular smooth muscle cells and endothelial cells at concentrations similar to those observed in clinical studies. As little as 0.1 mM homocysteine caused a 25% increase in DNA synthesis, and homocysteine at 1 mM increased DNA synthesis by 4.5-fold in rat aortic smooth muscle cells (RASMC). In contrast, homocysteine caused a dose-dependent decrease in DNA synthesis in human umbilical vein endothelial cells. Homocysteine increased mRNA levels of cyclin D1 and cyclin A in RASMC by 3- and 15-fold, respectively, indicating that homocysteine induced the mRNA of cyclins important for the reentry of quiescent RASMC into the cell cycle. Furthermore, homocysteine promoted proliferation of quiescent RASMC, an effect markedly amplified by 2% serum. The growth-promoting effect of homocysteine on vascular smooth muscle cells, together with its inhibitory effect on endothelial cell growth, represents an important mechanism to explain homocysteine-induced atherosclerosis.
Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, MA.
J C
JC
Tsai
M A
MA
Perrella
M
M
Yoshizumi
C M
CM
Hsieh
E
E
Haber
R
R
Schlegel
M E
ME
Lee
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001161:Arteriosclerosis / Q000097:blood / Q000209:etiology*; D001483:Base Sequence; D015415:Biomarkers / Q000097:blood; D001973:Bromodeoxyuridine; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D019938:Cyclin D1; D016213:Cyclins / Q000096:biosynthesis*; D004247:DNA / Q000096:biosynthesis; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D006710:Homocysteine / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015513:Oncogene Proteins / Q000096:biosynthesis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014471:Umbilical Veins
D015415:Biomarkers; D016213:Cyclins; D017931:DNA Primers; D015513:Oncogene Proteins; D012333:RNA, Messenger; D006710:Homocysteine; D019938:Cyclin D1; D004247:DNA; D001973:Bromodeoxyuridine; D013936:Thymidine