NO-independent cGMP regulation of vascular remodeling

血管重塑的不依赖于 cGMP 的调节

• 批准号: 7867858
• 负责人: DAVID A TULIS
• 金额: $ 35.62万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7867858
• 关键词: Address; Adenine; American; Animals; Attenuated; Basic Science; Blood Vessels; Carbon Monoxide; Cardiovascular system; Carotid Arteries; Cause of Death; Cell Culture System; Cell physiology; Cells; Clinical Research; Cyclic AMP; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotides; Data; Disease; Equilibrium; Event; Extracellular Matrix; Gelatinase A; Gelatinase B; Gene Delivery; Goals; Growth; Guanosine; Heart Diseases; Heme; Human; Injury; Intervention; Investigation; Knockout Mice; Laboratories; Ligands; Light; Matrix Metalloproteinases; Measures; Medial; Mediating; Modeling; Mus; Nitric Oxide; Perception; Pharmacology; Population; Protein Kinase; Public Health; RNA Interference; Rattus; Regulation; Research; Research Project Grants; Role; Route; Severities; Signal Transduction; Smooth Muscle Myocytes; Soluble Guanylate Cyclase; Testing; Therapeutic; Transgenic Model; Vascular Smooth Muscle; Vascular remodeling; Viral; base; cGMP-dependent protein kinase I; cell motility; insight; novel; response; statistics; tool; viral gene delivery

Vascular smooth muscle (VSM) cyclic guanosine 3',5'-moriophosphate (cGMP) serves as a critical regulator of many cellular functions that contribute to vessel growth after injury. Nitric oxide (NO) and carbon monoxide (CO) operate as soluble guanylate cyclase (sGC)-activating ligands for cGMP synthesis; however, limitations of NO and CO signaling warrant study into alternate, pathophysiologically relevant routes for cGMP control. Provocative new findings challenge the traditional notion that cGMP exerts vascular protection through cGMP-dependent protein kinase type (cGKI) and suggest that cGMP may operate via cAMP/cAK to promote vascular protection. Current studies in our laboratory focus on novel NOindependent approaches for cGMP control as significant basic science tools and as potential cardiovascular therapeutics. Preliminary data support a role for vascular growth control by NO-independent cGMP and suggest mechanistic involvement of matrix metalloproteinase (MMP)-2 and MMP-9. The long-term objective of this research project is to investigate strategies for cGMP control of VSM growth, and the central hypothesis of this proposal is that NO-independent cGMP protects against vascular growth and that this occurs through cAK signals. Two Specific Aims will be used to test this hypothesis: Aim 1 will analyze the roles of NO-independent cGMP and cGMP-directed cGKI/cAK signaling in attenuating vascular remodeling in the rat balloon injury and mouse wire denudation injury models. Aim 2 will examine matrix-based mechanisms including cell migration and MMP balance that underlie cGMP-mediated growth control in rat and mouse primary VSM cells. Pharmacology, RNA interference, and viral gene delivery approaches will be used, and conditional VSMspecific cGKI-deficient models will allow direct comparison of cGKI versus cAK mechanisms. Results are anticipated to provide insight into and further evidence for NO-independent cGMP control of the injury growth response in VSM and shed light upon cGMP-directed MMPs in mediating these events. Injuries and diseases of the heart and blood vessels are wide-ranging and very serious public health concerns, and statistics show they are still the major cause of death in American populations. We believe that results from these studies will shed light on some novel and promising strategies that could be used to minimize the severity of blood vessel injury and disease and may offer beneficial prospects for further study in basic science research and human-based clinical studies.

血管平滑肌（VSM）环状鸟嘌呤3'，5'-摩磷酸盐（CGMP）用作关键 许多细胞功能的调节剂，导致损伤后血管生长。一氧化氮（NO）和 碳一氧化碳（CO）作为可溶性鸟苷酸环化酶（SGC）活化的配体用于CGMP合成； 但是，NO和CO信号的局限性研究对替代性，病理学相关的局限性 CGMP控制的路由。挑衅性的新发现挑战了CGMP发挥的传统观念 通过CGMP依赖性蛋白激酶类型（CGKI）进行血管保护，并建议CGMP可能 通过CAMP/CAK操作以促进血管保护。我们实验室中的当前研究重点是新型Notectent CGMP控制作为重要的基础科学工具的方法，并作为潜在的心血管 疗法。初步数据支持无独立的CGMP血管生长控制的作用 提示基质金属蛋白酶（MMP）-2和MMP-9的机械参与。长期目标 该研究项目是调查CGMP控制VSM增长的策略，而中心 该提议的假设是，无独立的CGMP可以保护血管生长，这是 通过CAK信号发生。将使用两个具体目标来检验这一假设： AIM 1将分析无独立的CGMP和CGMP指导的CGKI/CAK信号的作用 大鼠球囊损伤和小鼠剥离损伤模型中的血管重塑。 AIM 2将检查基于矩阵的机制，包括细胞迁移和MMP平衡 CGMP介导的大鼠和小鼠初级VSM细胞的生长控制。 将使用药理学，RNA干扰和病毒基因递送方法，并有条件的VSMSpefific CGKI缺陷模型将可以直接比较CGKI与CAK机制。结果是 预计将提供有关无独立CGMP控制伤害的洞察力和进一步证据 VSM中的生长反应在介导这些事件时对CGMP指导的MMP进行了启示。 心脏和血管的伤害和疾病是广泛的，非常严重的公共卫生 担忧，统计数据表明，它们仍然是美国人口中的主要死亡原因。我们相信 这些研究的结果将阐明一些新颖而有希望的策略，这些策略可用于 最大程度地减少血管损伤和疾病的严重程度，并可能为进一步研究提供有益的前景 基础科学研究和基于人类的临床研究。