PFKFB3 in vascular remodeling

PFKFB3 在血管重塑中的作用

• 批准号: 9217824
• 负责人: YUQING HUO
• 金额: $ 57.01万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9217824
• 关键词: 6-Phosphofructo-2-kinase; 6-Phosphofructokinase; Adipocytes; Animal Model; Apoptosis; Attenuated; Bioenergetics; Blood Vessels; Cardiac Myocytes; Cell Proliferation; Cells; Collagen; Complex; Data; Development; Disease; Elements; Endothelial Cells; Endothelial Growth Factors; Enzymes; Fructose; Fructose-2,6-bisphosphatase; Gene Expression; Glycolysis; Goals; Growth Factor; HIF1A gene; Hepatocyte; Hypertrophy; Hypoxia; Knock-out; Lead; Lesion; Lung; Medial; Mediating; Mitogen-Activated Protein Kinases; Modeling; Mus; Muscle; Muscle Cells; Pathogenesis; Patients; Phosphorylation; Platelet-Derived Growth Factor; Play; Production; Progressive Disease; Protein Isoforms; Proteins; Pulmonary Hypertension; Pulmonary artery structure; Rattus; Resistance; Role; SU 5416; Smooth Muscle; Smooth Muscle Myocytes; Testing; Tissues; Vascular Diseases; Vascular Endothelial Growth Factors; Vascular Proliferation; Vascular Smooth Muscle; Vascular remodeling; Work; angiogenesis; base; design; fructose-6-phosphate; inhibitor/antagonist; mouse model; multidisciplinary; overexpression; pressure; prevent; primary pulmonary hypertension; pulmonary arterial hypertension; pulmonary artery endothelial cell; therapeutic target

PROJECT SUMMARY 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase isoform 3 (PFKFB3) is a critical glycolytic regulator in vascular cells. PFKFB3 catalyzes the synthesis of fructose-2, 6-bisphosphate (F2, 6P2) and the latter is the most potent activator for 6-phosphofructo-1-kinase (PFK-1), one of three rate-limiting enzymes for glycolysis. Proliferation of vascular cells including endothelial cells and vascular smooth muscle cells is the major feature of vascular remodeling in a variety of vascular diseases including pulmonary arterial hypertension (PAH). Ours and the work from others have demonstrated a critical role of endothelial PFKFB3 in angiogenesis. In our recent studies we have found the following: (1) PDGF/VEGF and hypoxia increase the protein level and activity of PFKFB3 in pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery endothelial cells (PAECs); (2) inhibition of PFKFB3 attenuates PDGF/VEGF- and hypoxia-induced collagen synthesis, hyperproliferation and resistance to apoptosis of PASMCs and PAECs; (3) hypoxia-induced pulmonary vascular remodeling was significantly suppressed in PFKFB3-/+ mice; (4) PFKFB3 protein levels are robustly increased in the smooth muscle cells and endothelial cells as well as plexiform lesions of pulmonary arteries of patients with idiopathic PAH. These data led us to hypothesize that PFKFB3 in vascular cells has a central role in vascular remodeling and suppression of PFKFB3 inhibits proliferation of vascular cells and further curbs the development of pulmonary arterial hypertension. The goal of this proposal is designed to use specific PFKFB3 inhibitor and tissue-specific PFKFB3 deletion mice to investigate whether and how PFKFB3 in vascular cells plays a crucial role in vascular remodeling of PAH. In Aim 1, we will investigate whether PDGF/VEGF and hypoxia increase PFKFB3 activity via HIF1α-mediated PFKFB3 gene expression and MAPK-mediated PFKFB3 phosphorylation in PASMCs and PAECs. In Aim 2, we will study whether and how lactate, arising from high PFKFB3 activity, elevates Akt activation, leading to collagen synthesis, hyperproliferation and resistance to apoptosis of PASMCs and PAECs. In Aim 3, we will examine whether pulmonary vascular remodeling is suppressed in mice with PFKFB3 deficiency in smooth muscle cells or endothelial cells, and in rat treated with a specific PFKFB3 inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2- propen-1-one (3PO). This proposal is highly translational. Completion of this project will advance a new PFKFB3-based paradigm for the suppression of vascular remodeling and may lead to a more effective and specific therapy of diseases associated with vascular remodeling.

项目概要 6-磷酸果糖-2-激酶/果糖-2, 6-双磷酸酶亚型 3 (PFKFB3) 是一种关键的糖酵解酶 血管细胞中的调节剂。 PFKFB3 催化果糖-2, 6-二磷酸 (F2, 6P2) 和 后者是 6-磷酸果糖-1-激酶 (PFK-1) 最有效的激活剂，是三种限速酶之一 糖酵解酶。血管细胞（包括内皮细胞和血管平滑肌）的增殖 肌细胞是多种血管疾病中血管重塑的主要特征，包括 肺动脉高压（PAH）。我们和其他人的工作已经证明了关键作用 内皮 PFKFB3 在血管生成中的作用。在我们最近的研究中，我们发现了以下内容：（1） PDGF/VEGF和缺氧增加肺动脉平滑肌PFKFB3的蛋白水平和活性 肌细胞（PASMC）和肺动脉内皮细胞（PAEC）； (2)抑制PFKFB3 减弱 PDGF/VEGF 和缺氧诱导的胶原蛋白合成、过度增殖和抗性 PASMCs 和 PAECs 凋亡； (3)缺氧引起的肺血管重塑显着 在 PFKFB3-/+ 小鼠中受到抑制； (4)平滑肌中PFKFB3蛋白水平显着增加 特发性肺动脉细胞和内皮细胞以及肺动脉丛状病变 多环芳烃。这些数据使我们推测血管细胞中的 PFKFB3 在血管生成中发挥核心作用。 PFKFB3的重塑和抑制抑制血管细胞增殖并进一步抑制 肺动脉高压的发展。该提案的目标旨在使用特定的 PFKFB3抑制剂和组织特异性PFKFB3缺失小鼠研究PFKFB3是否以及如何在 血管细胞在PAH的血管重塑中起着至关重要的作用。在目标 1 中，我们将调查是否 PDGF/VEGF 和缺氧通过 HIF1α 介导的 PFKFB3 基因表达增加 PFKFB3 活性 PASMC 和 PAEC 中 MAPK 介导的 PFKFB3 磷酸化。在目标 2 中，我们将研究是否和 PFKFB3 高活性产生的乳酸如何提高 Akt 激活，从而导致胶原蛋白合成， PASMCs 和 PAECs 的过度增殖和抗凋亡。在目标 3 中，我们将检查是否 平滑肌细胞 PFKFB3 缺乏的小鼠的肺血管重塑受到抑制，或 内皮细胞，以及用特定 PFKFB3 抑制剂 3-(3-吡啶基)-1-(4-吡啶基)-2- 处理的大鼠 丙烯-1-酮 (3PO)。该提案具有很强的转化性。该项目的完成将推动新的 基于 PFKFB3 的抑制血管重塑的范例可能会导致更有效的方法 以及与血管重塑相关的疾病的特异性治疗。