Vascular Smooth Muscle Signaling in Intermittent Hypoxia-Induced Pulmonary Hypertension

项目总结 慢性间歇性低氧致肺血管功能障碍 睡眠呼吸暂停患者的高血压(PHTN)。尽管越来越多的人认识到、流行和影响 这种紊乱，这种反应涉及的机制还知之甚少。 目前研究的总体目标是识别血管平滑肌(VSM)信号 蛋白激酶Cβ介导的肺血管收缩机制及其信号转导作用 CIH依赖增加血管收缩反应性、动脉重塑和pHTN的途径。基于 初步数据，我们的指导性假设是PKCβ通过一种新的 与支架蛋白PICK1相互作用、激活线粒体KATP(MitoKATP)的机制 通道、线粒体ROS(MitoROS)的产生和肌动蛋白聚合。此外，我们假设 此信号轴介导血管收缩反应性增强、动脉重塑和继发pHTN 啊哈。我们计划通过追求以下具体目标来检验这些假设： 1.确定PKCβ-mitoROS信号通路在增强动脉收缩反应性中的作用 脑出血后的肺动脉高压。 假说：PKCβ/mitoROS信号轴参与脑出血的进展和维持 VSM通过收缩和促有丝分裂作用诱导pHTN。 2.明确PKCβ刺激肺血管内皮细胞有丝分裂原产生的信号机制 脑出血后血管收缩敏感性增加。 假设：CIH通过依赖PICK1激活增强激动剂依赖的肺血管收缩 MitoKATP通道和随后的mitoROS产生 3.确定肌动蛋白聚合在PKCβ诱导的血管平滑肌收缩中的作用。 这是脑出血后肺血管收缩反应性增强的机制。 假设：CIH增强激动剂诱导的肺VSM钙敏化和血管收缩 通过PKC、β和丝裂原依赖的肌动蛋白聚合。 我们预计这个项目将定义一种涉及PKCβ的VSM信令的创新范例， 肺循环所特有的丝裂原生成、肌动蛋白聚合和钙敏化， 以及在临床相关的睡眠呼吸暂停啮齿动物模型中，该通路在pHTN发生中的作用。 这些研究具有重要意义，因为它们预计将垂直影响我们对 参与CIH诱导的pHTN的血管收缩机制，因此有可能产生独特的 睡眠呼吸暂停相关的pHTN和其他心血管和代谢疾病的治疗策略 其中PKCβ信令是核心玩家。

PROJECT SUMMARY Pulmonary vascular dysfunction resulting from chronic intermittent hypoxia (CIH) leads to pulmonary hypertension (pHTN) in patients with sleep apnea. Despite the growing recognition, prevalence, and impact of this disorder, the mechanisms involved in this response are poorly understood. The overall objective of the current study is to identify vascular smooth muscle (VSM) signaling mechanisms responsible for PKCβ-mediated pulmonary vasoconstriction, and the role of this signaling pathway in CIH-dependent increases in vasoconstrictor reactivity, arterial remodeling and pHTN. Based on preliminary data, our guiding hypothesis is that PKCβ mediates pulmonary vasoconstriction through a novel mechanism involving interaction with the scaffolding protein PICK1, activation of mitochondrial KATP (mitoKATP) channels, mitochondrial ROS (mitoROS) generation, and actin polymerization. Furthermore, we hypothesize that this signaling axis mediates enhanced vasoconstrictor reactivity, arterial remodeling and pHTN following CIH. We plan to test these hypotheses by pursuing the following specific aims: 1. Determine the role of PKCβ–mitoROS signaling in enhanced arterial constrictor reactivity and pulmonary hypertension following CIH. Hypothesis: The PKCβ/mitoROS signaling axis contributes to the progression and maintenance of CIH- induced pHTN through contractile and mitogenic actions in VSM. 2. Define the signaling mechanism by which PKCβ stimulates mitoROS generation in pulmonary VSM and increased vasoconstrictor sensitivity after CIH. Hypothesis: CIH enhances agonist-dependent pulmonary vasoconstriction via PICK1-dependent activation of mitoKATP channels and subsequent mitoROS production 3. Establish the contribution of actin polymerization to PKCβ-induced VSM contraction and the role of this mechanism in augmented pulmonary arterial vasoconstrictor reactivity following CIH. Hypothesis: CIH augments agonist-induced pulmonary VSM Ca2+ sensitization and vasoconstriction through PKCβ and mitoROS-dependent actin polymerization. We anticipate that this project will define an innovative paradigm of VSM signaling involving PKCβ, mitoROS generation, actin polymerization and Ca2+ sensitization that is unique to the pulmonary circulation, and the role of this pathway in the development of pHTN in a clinically relevant rodent model of sleep apnea. These studies are significant because they are expected to vertically impact our understanding of vasoconstrictor mechanisms that contribute to CIH-induced pHTN, and therefore have potential to yield unique treatment strategies for sleep apnea-associated pHTN and other cardiovascular and metabolic disorders in which PKCβ signaling is a central player.