REGULATION OF PA SMC PROLIFERATIVE RESPONSE TO HYPOXIA

传统观点认为缺氧性肺动脉（PA）生长 平滑肌细胞（SMC）在慢性肺动脉高压是一个直接的 由于持续的血管收缩和由此产生的机械应力， 内皮损伤和局部生长因子产生。虽然缺氧 一般认为不直接促进PA SMC增殖，我们 发现了一种独特的协同机制， 直接增强和维持血管壁中的增殖信号。 在用机械应力或肽有丝分裂原“引发”后，PA SMC 获得对缺氧做出反应的增殖能力。我们现在有 有证据表明PA的增殖反应存在异质性， 平滑肌细胞亚群对缺氧的反应及其缺氧的程度 血管损伤后生长增强。然而， 调节PA、SMC和 允许这种新形式的增殖协同作用的发生， 明白我们已经生成的数据表明， 蛋白激酶C（PKC）的钙依赖性α亚型--一种重要的 增殖性激酶--在这一过程的启动中具有独特的重要性， 低氧生长然而，PKC-α激活在 调节缺氧增殖的程度尚不清楚。许多 调节PKC-α活化的机制还不清楚。 我们也有数据表明， PKC-α的激活还不清楚。我们也有数据表明 PKC-α表达增加与增强的 可能存在缺氧生长。调节表达的机制， PKC-α的降解是未知的。因此，总体目标是 这项建议是为了确定PKC-α的激活和表达 控制PA SMC缺氧生长，并阐明调节 这些细胞中PKC-α的激活和表达。具体目标 将测试中心假设，即：激活和表达PKC- α是PA SMC增殖反应的关键决定因素， 体内和体外缺氧。该项目将增加我们的 理解控制协同作用、异质性和 慢性肺损伤大鼠肺动脉平滑肌细胞缺氧性生长 肺动脉高压它还将产生有用的新信息， PKC的基础生物学。信号转导中的几个新概念 包括激酶内异质性的重要性 家族、磷酸酶和细胞内蛋白酶在调节 激酶活性和表达，激酶基因表达调节 细胞外刺激，激酶级联内和之间的串扰，以及 上游激酶与选定的细胞周期中间产物之间的相互作用 和转录因子。

The traditional view has been that hypoxic growth of pulmonary artery (PA) smooth muscle cells (SMC) in chronic pulmonary hypertension is a direct consequence of sustained vasoconstriction and resulting mechanical stress, endothelial injury, and local growth factor production. Although hypoxia is not generally thought to directly promote proliferation of PA SMC, we have discovered a unique synergistic mechanism by which hypoxia can directly augment and sustain proliferative signals in the vessel wall. Following "priming" with mechanical stress or peptide mitogens, PA SMC acquire the ability to proliferate in response to hypoxia. We now have evidence that there is heterogeneity in the proliferative response of PA SMC subpopulations to hypoxia and that the magnitude of their hypoxic growth is enhanced following vascular injury. However, the mechanisms that regulate the expression of this hypoxia-sensitive phenotype in PA, SMC and permit this novel form of proliferative synergy to occur are not understood. We have generated data that suggests that activation of the calcium dependent alpha isoform of protein kinase C (PKC)--an important proliferative kinases--is uniquely important in the initiation of this hypoxic growth. However, the role that PKC-alpha activation plays in regulating the magnitude of hypoxic proliferation is not clear. Many of the mechanisms that regulate PKC-alpha activation are not well understood. We also have data suggesting a direct link between increased expression of PKC-alpha activation are not well understood. We also have data suggesting a direct link between increased expression of PKC-alpha and augmented hypoxic growth may exist. The mechanisms that regulate the expression and degradation of PKC-alpha are not known. Therefore, the overall goal of this proposal is to determine if PKC-alpha activation and expression control PA SMC hypoxic growth and to elucidate mechanisms that regulate activation and expression of PKC-alpha in these cells. The specific aims will test the central hypothesis that: Activation and expression of PKC- alpha are critical determinants of PA SMC proliferative response to hypoxia in vivo and in vitro. This project should increase our understanding of the mechanisms that control synergy, heterogeneity, and injury-induced upregulation in hypoxic growth of PA SMC in chronic pulmonary hypertension. It will also generate useful new information on the basic biology of PKC. Several emerging concepts in signal transduction will be addressed including the importance of heterogeneity within kinase families, phosphatases and intracellular protease in the regulation of kinase activity and expression, modulation of kinase gene expression by extracellular stimuli, cross talk within and between kinase cascades, and interaction between upstream kinases and selected cell cycle intermediates and transcription factors.