VASCULAR SMOOTH-MUSCLE CELL HYPERTROPHY VS HYPERPLASIA - AUTOCRINE TRANSFORMING GROWTH FACTOR-BETA-1 EXPRESSION DETERMINES GROWTH-RESPONSE TO ANGIOTENSIN-II
VASCULAR SMOOTH-MUSCLE CELL HYPERTROPHY VS HYPERPLASIA - AUTOCRINE TRANSFORMING GROWTH FACTOR-BETA-1 EXPRESSION DETERMINES GROWTH-RESPONSE TO ANGIOTENSIN-II
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DOI：
10.1172/jci115881
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发表时间：
1992-08-01
影响因子：
15.9
通讯作者：
DZAU, VJ
中科院分区：
文献类型：
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作者：
GIBBONS, GH;PRATT, RE;DZAU, VJ
我们实验室的最新观察表明，血管紧张素II（Ang II）是一种双功能的血管平滑肌细胞（VSMC）生长调节剂，能够诱导肥大或抑制有丝分裂原刺激的DNA合成。由于转化生长因子-β-1（TGF-β-1）对VSMC生长具有类似的双功能作用，我们假设TGF-β-1的自分泌产生可能介导Ang II的生长调节作用。事实上，这项研究表明，血管紧张素II诱导TGF-β-1 mRNA水平在4小时内，这是依赖于从头蛋白质合成，似乎是由蛋白激酶C（PKC）的激活介导的几倍增加。Ang II不仅刺激潜在TGF-β 1的合成，而且促进其转化为生物活性形式，如通过生物测定所测量的。血管紧张素II和对照IgG共孵育的VSMCs没有显着的促有丝分裂作用。然而，Ang II和抗TGF-β-1抗体的共同施用显著刺激DNA合成和细胞增殖。我们的结论是：（a）Ang II通过涉及从头蛋白质合成的PKC依赖性途径诱导增加的TGF-β 1基因表达;（B）Ang II促进潜伏TGF-β 1向其生物活性形式的转化;（c）Ang II通过激活增殖和抗增殖途径调节VSMC生长;和（d）自分泌活性TGF-β 1似乎是VSMC通过肥大或增生生长的重要决定因素。
Recent observations in our laboratory suggest that angiotensin II (Ang II) is a bifunctional vascular smooth muscle cell (VSMC) growth modulator capable of inducing hypertrophy or inhibiting mitogen-stimulated DNA synthesis. Because transforming growth factor-beta-1 (TGF-beta-1) has similar bifunctional effects on VSMC growth, we hypothesized that autocrine production of TGF-beta-1, may mediate the growth modulatory effects of Ang II. Indeed, this study demonstrates that Ang II induces a severalfold increase in TGF-beta-1 mRNA levels within 4 h that is dependent on de novo protein synthesis and appears to be mediated by activation of protein kinase C (PKC). Ang II not only stimulates the synthesis of latent TGF-beta-1 but also promotes its conversion to the biologically active form as measured by bioassay. The coincubation of VSMCs with Ang II and control IgG has no significant mitogenic effect. However, the co-administration of Ang II and the anti-TGF-beta-1 antibody stimulates significantly DNA synthesis and cell proliferation. We conclude that: (a) Ang II induces increased TGF-beta-1 gene expression via a PKC dependent pathway involving de novo protein synthesis; (b) Ang II promotes the conversion of latent TGF-beta-1 to its biologically active form; (c) Ang II modulates VSMC growth by activating both proliferative and antiproliferative pathways; and (d) Autocrine active TGF-beta-1 appears to be an important determinant of VSMC growth by hypertrophy or hyperplasia.