Counteracting effects of high density lipoprotein-cholesterol subfractions on statin-induced growth arrest.
An important issue in atherosclerosis is the timing of intimal microvascular formation and its relation to the initiation of plaque formation. Monocytes and endothelial cells (ECs) are important cell components in these steps. Statins not only reduce atherogenic low density lipoprotein cholesterol, they also increase high density lipoprotein-cholesterol (HDL). Although a higher concentration of statin has an anti-proliferative effect, HDL is potentially mitogenic. Therefore, we examined the opposing effects of statin, Apo-AI, HDL and HDL fractions on cell proliferation and apoptosis in monocytes and on angiogenesis in ECs. A high concentration of simvastatin inhibited monocyte proliferation as evaluated by counting cell numbers using a hematocytometer. This inhibition was mainly blocked by the HDL3 subfraction. The same concentration of simvastatin induced apoptosis as assessed by the fluorescence-labeled annexin-V method through caspase-3 activation in monocytes. HDL inhibited simvastatin-induced apoptosis. In addition, HDL blocked simvastatin-inhibited angiogenesis in an in vitro model of EC tube formation. In conclusion, the compensatory balance between the effects of statin and HDL may play an important role in the formation of atherosclerotic lesions by affecting proliferation and apoptosis in monocytes and angiogenesis in ECs.
Fujino
Masahiro
M
Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
Miura
Shin-Ichiro
S
Tanigawa
Hiroyuki
H
Matsuo
Yoshino
Y
Saku
Keijiro
K
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000187:drug effects / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D008076:Cholesterol, HDL / Q000187:drug effects* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology; D020298:U937 Cells / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases