Phosphodiesterase 3 and Atherosclerosis

磷酸二酯酶 3 与动脉粥样硬化

• 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
• 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

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， 血管壁重塑。越来越多的证据表明，直接病理生物学事件在血管壁发挥作用， 在动脉粥样硬化中的重要作用。血管内皮细胞（EC）和平滑肌细胞（VSMC）都是 是炎性细胞因子的重要靶点，也能够产生大量的细胞因子， 趋化因子和粘附分子。动脉粥样硬化的发展可能涉及微血管的扰动， 抗动脉粥样硬化信号传导（如一氧化氮（NO）、C型利钠尿肽）与抗动脉粥样硬化信号传导之间的稳态平衡 肽（CNP）和环核苷酸）和促动脉粥样硬化信号传导（如TNF α和Ang II）。 环核苷酸磷酸二酯酶（cyclicnucleotidephosphodiesterases，PDEs）在调节细胞内环核苷酸（cyclicnucleotide，cAMP）水平中起着重要作用 和cGMP）水平和通过环核苷酸降解的区室化。我们最近的研究表明 NO和CNP通过抑制VSMCs中NF-κ B依赖性炎症分子的表达， 磷酸二酯酶3（PDE 3）的cGMP依赖性抑制。PDE 3是存在的主要cAMP水解PDE NO-cGMP和CNP-cGMP抑制VSMC的PKA活性， NF-κ B活化和炎性分子表达。此外，抑制PDE 3功能 特异性阻断TNF α刺激的NF-κ B活化和炎性分子表达。这些 结果表明，PDE 3活性是VSMC中炎性基因表达的关键调节因子， cGMP介导的PDE 3活性抑制是NO-cGMP抗炎作用的机制， VSMC中的CNP-cGMP。目的：探讨PDE 3在VSMC炎症分子调节中的作用 表达与动脉粥样硬化形成的关系，我们提出以下三个目的：目的1：鉴定特异性亚型 PDE 3参与调节VSMC中NF-κ B依赖性炎症分子的表达。目的 2：确定PDE 3在离体培养的VSMC中调节炎性分子表达的作用 使用器官培养系统的容器。目的3：确定VSMC过表达PDE 3亚型的作用 动脉粥样硬化的实验。