Crosstalk Between Metabolism and Inflammation in Pulmonary Hypertension

肺动脉高压代谢与炎症之间的串扰

• 批准号: 8800338
• 负责人: Kurt R. Stenmark
• 金额: $ 49.22万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8800338
• 关键词: Address; Affinity; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Binding; Blood Vessels; C-Terminal Binding Protein 1; C-terminal binding protein; Cattle; Cells; Chronic; Clinical Management; Complex; DNA Binding; Data; Disease; Environment; Enzymes; Exhibits; Fibroblasts; Figs - dietary; Gene Expression Profile; Genes; Genetic Transcription; Goals; Histones; Human; Hypoxia; IL6 gene; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-10; Investigation; Link; Lung; Macrophage Activation; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Methodology; Molecular; Mus; NADH; Oxidation-Reduction; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Process; Proteins; Pulmonary Hypertension; Pulmonary artery structure; Reagent; Recruitment Activity; Repression; Research; Resistance; Rodent; Role; STAT3 gene; Sensory; Signal Induction; Signal Transduction; Syndrome; Testing; Therapeutic Intervention; Transcription Repressor/Corepressor; Tunica Adventitia; Vascular Diseases; Vascular remodeling; aerobic glycolysis; cancer cell; cell behavior; cell type; chemokine; cytokine; design; histone modification; hypoxia inducible factor 1; in vivo; innovation; macrophage; novel; prevent; public health relevance; response; sensor; transcription factor

DESCRIPTION (provided by applicant): Inflammatory processes are increasingly appreciated to play a critical role in vascular remodeling. This proposal addresses the role of inflammation, and specifically the role of macrophages in the vascular remodeling that characterize hypoxic forms of pulmonary hypertension (PH). Observations in most forms of PH show that macrophages accumulate primarily in the adventitial and perivascular regions of the vessel. Strong preliminary data demonstrate that fibroblasts resident in the adventitia of PH vessels undergo significant metabolic changes leading to increases in intracellular NADH concentration and subsequent activation of the transcriptional repressor C-terminal binding protein 1 (CtBP1), a transcriptional redox sensor with high binding affinity for NADH. CtBP1 acts specifically to repress expression of anti-inflammatory genes including, hemoxygenase-1 (HMOX-1). These "activated" fibroblasts recruit and activate macrophages toward a pro- inflammatory/remodeling phenotype largely through IL6, STAT3, HIF1 signaling and induction of aerobic glycolysis. We propose that both the pro-inflammatory fibroblast and fibroblast activated macrophage phenotype in hypoxic PH is driven by CtBP1. During hypoxia and/or in conditions of aerobic glycolysis we have shown that NADH-activated CtBP1 acts as a transcriptional co-repressor and complexes with DNA-binding transcription factors and histone modification enzymes (HDACs, HMTs). CtBP1 therefore links the metabolic status of the cell to specific coordination of gene transcription and, as we have shown, exerts a dominant role in determining cell behavior. We now address the novel hypothesis that CtBP1 drives the pro-inflammatory functions of fibroblasts in PH, leading to fibroblast-mediated macrophage activation. The inflammatory environment, caused by the interaction of fibroblasts and macrophages, leads to PH and pulmonary vascular remodeling. Our approach relies on in vitro and in vivo studies using lung adventitial fibroblasts and primary na�ve macrophages from hypoxic cows, rodents, and human controls and PH patients, and novel genetically modified mice. AIM 1: Determine the role of CtBP1 in "locking" the fibroblast into a pro-inflammatory phenotype. AIM 2: Determine the role of CtBP1 in controlling the pro-inflammatory/pro-remodeling phenotype of fibroblast-activated macrophages. AIM 3: Determine whether CtBP1/HO-1 signaling can be targeted in a cell-type-specific manner in vivo to prevent or even reverse hypoxia-induced PH. Our investigations will ultimately provide key data in elucidating the role of inflammation as a cause/contributor, a bystander, or whether or when it is simply the end result of the disease process. This is a critica step to advance our understanding of chronic pulmonary vascular disease in order to significantly impact the clinical management of PH.

描述（由申请人提供）：越来越多的人认识到炎症过程在血管重塑中发挥着关键作用。该提案阐述了炎症的作用，特别是巨噬细胞在以肺动脉高压（PH）的缺氧形式为特征的血管重塑中的作用。对大多数 PH 形式的观察表明，巨噬细胞主要积聚在血管的外膜和血管周围区域。强有力的初步数据表明，存在于 PH 血管外膜中的成纤维细胞会发生变化。显着的代谢变化导致细胞内 NADH 浓度增加，并随后激活转录抑制因子 C 末端结合蛋白 1 (CtBP1)，CtBP1 是一种与 NADH 具有高结合亲和力的转录氧化还原传感器，可特异性抑制抗炎基因（包括）的表达。这些“激活的”成纤维细胞主要通过 IL6、STAT3 募集并激活巨噬细胞以形成促炎/重塑表型。 HIF1 信号传导和有氧糖酵解的诱导 我们认为，缺氧 PH 中的促炎成纤维细胞和成纤维细胞激活的巨噬细胞表型都是由 CtBP1 驱动的，我们已经证明，在缺氧和/或有氧糖酵解条件下，NADH 激活的 CtBP1 发挥作用。转录辅阻遏物以及与 DNA 结合转录因子和组蛋白修饰酶（HDAC、HMT）的复合物。因此，CtBP1 将细胞的代谢状态与基因转录的特定协调联系起来，并且正如我们所表明的，在决定细胞行为方面发挥着主导作用，我们现在提出了新的假设，即 CtBP1 驱动 PH 中成纤维细胞的促炎功能。导致成纤维细胞介导的巨噬细胞激活。由成纤维细胞和巨噬细胞相互作用引起的炎症环境导致 PH 和肺血管重塑。我们的方法依赖于使用肺的体外和体内研究。来自缺氧牛、啮齿动物、人类对照和PH患者以及新型转基因小鼠的外膜成纤维细胞和初级巨噬细胞AIM 1：确定CtBP1在“锁定”成纤维细胞成促炎表型中的作用AIM 2：确定。 CtBP1 在控制成纤维细胞激活的巨噬细胞促炎症/促重塑表型中的作用：确定 CtBP1/HO-1 信号传导是否可以在体内以细胞类型特异性方式靶向，以预防甚至逆转缺氧诱导的 PH。我们的研究最终将提供关键数据，阐明炎症作为原因/贡献者的作用，旁观者，或者是否或何时仅仅是疾病过程的最终结果，这是加深我们对慢性肺血管疾病的理解以显着影响 PH 临床管理的关键一步。