INDUCTION OF PLATELET-DERIVED GROWTH FACTOR-A-CHAIN AND C-MYC GENE EXPRESSIONS BY ANGIOTENSIN-II IN CULTURED RAT VASCULAR SMOOTH-MUSCLE CELLS
INDUCTION OF PLATELET-DERIVED GROWTH FACTOR-A-CHAIN AND C-MYC GENE EXPRESSIONS BY ANGIOTENSIN-II IN CULTURED RAT VASCULAR SMOOTH-MUSCLE CELLS
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DOI：
10.1172/jci114032
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发表时间：
1989-04-01
影响因子：
15.9
通讯作者：
DZAU, VJ
中科院分区：
文献类型：
--
作者：
NAFTILAN, AJ;PRATT, RE;DZAU, VJ
最近，血管紧张素II （Ang II）已被证明可引起培养的静息大鼠主动脉平滑肌（RASM）细胞肥大。这一观察结果以及血管壁中血管紧张素原mRNA的证明使我们假设血管紧张素在低血压血管肥大中起作用。为了进一步研究可能的分子机制，我们研究了Ang II对已知参与细胞生长反应的两个基因表达的影响。将接近融合的RASM细胞暴露于指定的无血清培养基中48小时，使其处于静止状态。Ang II（10-6至10-11 M）在30分钟内诱导原癌基因c-myc mRNA，并持续6小时。有趣的是，在添加Ang II后6小时，血小板衍生生长因子（PDGF） a链mRNA表达升高，在9小时达到峰值，并持续11小时。这伴随着培养基中PDGF浓度增加15-20倍。这些作用是剂量依赖性的，并被萨拉拉西辛阻断。而环己亚胺抑制蛋白质合成导致c-myc mRNA的稳定，环己亚胺消除PDGF a链mRNA的升高。综上所述，我们的数据表明，RASM细胞暴露于Ang II导致c-myc和PDGF a链mRNA表达的顺序激活。原同源基因和生长因子基因的顺序激活可能是血管紧张素诱导平滑肌生长和肥大的重要机制。
Recently, angiotensin II (Ang II) has been shown to cause hypertrophy of cultured quiescent rat aortic smooth muscle (RASM) cells. This observation along with the demonstration of angiotensinogen mRNA in the vessel wall has led us to postulate a role for vascular angiotenin in hypotensive blood vessel hypertrophy. To investigate further the possible molecular mechanisms, we examined the effect of Ang II on the expression of two genes known to be involved with cellular growth response. Near-confluent RASM cells were made quiescent by 48-h exposure to a defined serum-free medium. Ang II (10-6 to 10-11 M) resulted in an induction of the protooncogene c-myc mRNA within 30 min which persisted for 6 h. Interestingly, 6 h after the addition of Ang II, platelet-derived growth factor (PDGF) A-chain mRNA expression was elevated, peaked in 9 h, and persisted for 11 h. This was accompanied with a 15-20 fold increase in PDGF concentration in the culture medium. These effects were dose-dependent and were blocked by saralasin. Whereas the inhibition of protein synthesis by cycloheximide resulted in a stabilization of c-myc mRNA, cycloheximide abolished the elevation of the PDGF A-chain mRNA. Taken together, our data show that exposure of RASM cells to Ang II results in the sequential activation of c-myc and PDGF A-chain mRNA expressions. This sequential activation of protoocongene and growth factor gene may be an important mechanism in angiotensin-induced smooth muscle growth and hypertrophy.