Phosphodiesterase 3 and Atherosclerosis

磷酸二酯酶 3 与动脉粥样硬化

基本信息

批准号：
7485124
负责人：
Bradford C Berk
金额：
$ 30.24万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7485124
关键词：
Acceleration Anti-Inflammatory Agents Anti-inflammatory Arterial Fatty Streak Atherosclerosis C-Type Natriuretic Peptide CCL2 gene Cell Adhesion Molecules Chronic Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP Cyclic Nucleotides Development Endothelial Cells Endothelium Equilibrium Event Figs - dietary Functional disorder Gene Expression Genetic Transcription Homeostasis Hydrolysis In Vitro Individual Inflammatory Inflammatory Response Mediating Mus NF-kappa B Natriuretic Peptides Nitric Oxide Nucleotides Organ Culture Techniques Play Process Protein Isoforms Protein Overexpression Regulation Role Signal Transduction Smooth Muscle Myocytes System Testing Therapeutic Agents Tissue Therapy Tissues Transgenic Mice Tumor Necrosis Factor-alpha Vascular Cell Adhesion Molecule-1 Vascular Endothelial Cell Vascular remodeling chemokine cytokine diethylstilbestrol monophosphate human TNF protein novel strategies novel therapeutics phosphoric diester hydrolase promoter

项目摘要

The progression of atherosclerotic lesions is believed to be a chronic inflammatory process involving vascular remodeling of the vessel wall. There is increasing evidence that direct pathobiological events in the vessel wall play an important role in atherosclerosis. Vascular endothelial cell (EC) and smooth muscle cell (VSMC) are both important targets for inflammatory cytokines and also capable of producing significant amounts of cytokines, chemokines, and adhesion molecules. The development of atherosclerosis may involve the perturbation of the homeostatic balance between the anti-atherosclerotic signaling (such as nitric oxide (NO), C-type natriuretic peptide (CNP), and cyclic nucleotides) and the pro-atherosclerotic signaling (such as TNF alpha and Ang II). Cyclic nucleotide phosphodiesterases (PDEs) play critical roles in regulating intracellular cyclic nucleotide (cAMP and cGMP) levels and compartmentalization via degradation of cyclic nucleotides. We have recently shown that NO and CNP inhibited NF-kappaB-dependent inflammatory molecule expression in cultured VSMCs via a cGMP-dependent inhibition of phosphodiesterase 3 (PDE3). PDE3 is the major cAMP-hydrolyzing PDE present in VSMC and its inhibition by NO-cGMP and CNP-cGMP results in increased PKA activity, which inhibits NF-kappaB activation and inflammatory molecule expression. Furthermore inhibition of PDE3 function specifically blocked TNFalpha-stimulated NF-kappaB activation and inflammatory molecule expression. These results suggest that PDE3 activity is a critical regulator of inflammatory gene expression in VSMC and that cGMP-mediated inhibition of PDE3 activity is the mechanism of the anti-inflammatory effects of NO-cGMP and CNP-cGMP in VSMC. To determine the role of PDE3 in the regulation of VSMC inflammatory molecule expression and atherosclerosis formation, we propose the following three aims: Aim 1: Identify the specific isoform of PDE3 involved in regulating NF-kappaB-dependent inflammatory molecule expression in VSMC in vitro. Aim 2: Determine the role of PDE3 in the regulation of inflammatory molecule expression in VSMC in ex vivo cultured vessels using the organ culture system. Aim 3: Determine the effect of VSMC overexpression of a PDE3 isoform on atherosclerosis using genetically modified mice.

动脉粥样硬化病变的进展被认为是涉及血管的慢性炎症过程血管壁的重塑。越来越多的证据表明血管壁发挥直接病理生物学事件在动脉粥样硬化中起重要作用。血管内皮细胞（EC）和平滑肌细胞（VSMC）都是炎症细胞因子的重要靶标，也能够产生大量细胞因子，趋化因子和粘附分子。动脉粥样硬化的发生可能与动脉粥样硬化的扰动有关。抗动脉粥样硬化信号（如一氧化氮 (NO)、C 型利钠尿剂）之间的稳态平衡肽（CNP）和环核苷酸）和促动脉粥样硬化信号传导（例如 TNF α 和 Ang II）。环核苷酸磷酸二酯酶 (PDE) 在调节细胞内环核苷酸 (cAMP) 中发挥关键作用和 cGMP）水平和通过环核苷酸降解进行区室化。我们最近表明 NO 和 CNP 通过抑制培养的 VSMC 中 NF-κB 依赖性炎症分子的表达磷酸二酯酶 3 (PDE3) 的 cGMP 依赖性抑制。 PDE3 是主要的 cAMP 水解 PDE VSMC 中的 NO-cGMP 和 CNP-cGMP 抑制导致 PKA 活性增加，从而抑制 NF-κB 激活和炎症分子表达。此外，抑制 PDE3 功能特异性阻断 TNFα 刺激的 NF-κB 激活和炎症分子表达。这些结果表明 PDE3 活性是 VSMC 中炎症基因表达的关键调节因子 cGMP 介导的 PDE3 活性抑制是 NO-cGMP 抗炎作用的机制 VSMC 中的 CNP-cGMP。确定PDE3在VSMC炎症分子调节中的作用表达和动脉粥样硬化形成，我们提出以下三个目标：目标 1：识别特定亚型 PDE3 参与调节体外 VSMC 中 NF-κB 依赖性炎症分子的表达。目的 2：确定PDE3对离体培养的VSMC炎症分子表达的调节作用使用器官培养系统的容器。目标 3：确定 PDE3 同工型 VSMC 过表达的影响使用转基因小鼠研究动脉粥样硬化。