REGULATION OF PA SMC PROLIFERATIVE RESPONSE TO HYPOXIA

传统的观点认为，缺氧性的肺动脉(PA)生长 平滑肌细胞(SMC)在慢性肺动脉高压中的直接作用 持续的血管收缩和由此产生的机械应力的后果， 内皮损伤和局部生长因子的产生。虽然缺氧 一般认为不会直接促进PA SMC的增殖，我们 发现了一种独特的协同机制，通过这种机制，缺氧可以 直接增强和维持血管壁上的增殖信号。 在机械应激或多肽有丝分裂原“启动”后，PA SMC 获得对低氧作出反应的增殖能力。我们现在有 PA的增殖反应存在异质性的证据 SMC亚群对缺氧及其缺氧程度的影响 血管损伤后，生长得到促进。然而，这些机制 调节这种缺氧敏感表型在PA、SMC和 允许这种新形式的增殖性协同作用发生并不是 明白了。我们已经生成的数据表明，激活 钙依赖的蛋白激酶Cα亚型--一种重要的 增殖蛋白--在这一过程中起着非常重要的作用。 低氧生长。然而，PKC-α激活在其中所起的作用 对缺氧性增殖的程度进行调控尚不清楚。许多. 调节PKC-α激活的机制还不是很清楚。 我们也有数据表明，表达增加的 PKC-α的激活还不是很清楚。我们还有数据表明 PKC-α表达增强与增强之间的直接联系 可能存在低氧生长。调节基因表达和基因表达的机制 PKC-α的降解情况尚不清楚。因此，总的目标是 该建议旨在确定PKC-α的激活和表达 控制PA-SMC低氧生长及其调控机制 PKC-α在这些细胞中的激活和表达。具体目标 将检验以下中心假设：PKC-1的激活和表达 α是PA SMC增殖反应的关键决定因素 体内和体外缺氧。这个项目应该会增加我们的 了解控制协同、异质和 慢性损伤诱导的PA-SMC缺氧性生长上调 肺动脉高压。它还将产生关于以下方面的有用新信息 PKC的基础生物学。信号转导中的几个新兴概念 将讨论的内容包括激酶内异质性的重要性 家族、磷酸酶和胞内蛋白水解酶在细胞周期调控中的作用 蛋白激酶的活性和表达，对蛋白激酶基因表达的调控 细胞外刺激，激酶级联内部和之间的串扰，以及 上游激酶与部分细胞周期中间产物的相互作用 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.