Molecular basis of α-tocopherol control of smooth muscle cell proliferation
Molecular basis of α-tocopherol control of smooth muscle cell proliferation
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DOI：
10.1002/biof.5520070102
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发表时间：
1998-01-01
期刊：
影响因子：
6
通讯作者：
Spycher, Stefan
中科院分区：
文献类型：
--
作者：
Azzi, Angelo;Aratri, Elisabetta;Spycher, Stefan
大鼠和人类血管平滑肌细胞增殖对-生育酚特别敏感，而对-生育酚则不敏感。前者，而不是后者，能够以剂量依赖的方式限制增殖和抑制蛋白激酶C活性。这种现象发生在10-50 μ m的浓度范围内，β -生育酚与α -生育酚一起，可以阻止细胞生长和抑制蛋白激酶C。-生育酚增加蛋白激酶C分子的从头合成。然而，由于α -生育酚存在时蛋白激酶C的磷酸化降低，酶的特异性活性降低。对蛋白激酶C亚型特异性抑制剂和沉淀抗体的实验表明，α -生育酚唯一影响的亚型是蛋白激酶C- α。-生育酚的作用被冈田酸阻止，表明PP2A型磷酸酶负责在-生育酚存在下产生的蛋白激酶c - α去磷酸化。在基因水平上，α -生育酚而非β -生育酚诱导α -原肌球蛋白基因转录和蛋白表达的短暂激活。有人提出，α -生育酚通过激活磷酸酶PP2A抑制蛋白激酶C活性，通过改变基因表达控制平滑肌细胞增殖。
Rat and human vascular smooth muscle cell proliferation is specifically sensitive to alpha-tocopherol, but not beta-tocopherol. The former, but not the latter, is capable of limiting proliferation and inhibiting protein kinase C activity in a dose-dependent manner. The phenomenon occurs at concentrations in the range 10-50 mu M. beta-tocopherol addition together with alpha-tocopherol, prevents both cell growth and protein kinase C inhibition. alpha-tocopherol increases de novo synthesis of protein kinase C molecules. The enzyme specific activity, however, is diminished, due to a decreased phosphorylation of protein kinase C, occurring in the presence of alpha-tocopherol. Experiments with protein kinase C isoform-specific inhibitors and precipitating antibodies show that the only isoform affected by alpha-tocopherol is protein kinase C-alpha. The effect of alpha-tocopherol is prevented by okadaic acid indicating a phosphatase of the PP2A type as responsible for protein kinase C-alpha dephosphorylation produced in the presence of alpha-tocopherol. At a gene level alpha-tocopherol but not beta-tocopherol induces a transient activation of alpha-tropomyosin gene transcription and protein expression. It is proposed that, by inhibiting protein kinase C activity via an activation of a phosphatase PP2A, alpha-tocopherol controls smooth muscle cell proliferation through changes in gene expression.