NO-independent cGMP regulation of vascular remodeling

血管重塑的不依赖于 cGMP 的调节

基本信息

批准号：
8462423
负责人：
DAVID A TULIS
金额：
$ 8.21万
依托单位：
EAST CAROLINA UNIVERSITY
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：
2007-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8462423
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 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 cell motility insight novel response statistics tool viral gene delivery

项目摘要

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) 环鸟苷 3',5'-鸟磷酸 (cGMP) 是一种关键的许多细胞功能的调节剂，有助于损伤后血管的生长。一氧化氮 (NO) 和一氧化碳 (CO) 作为可溶性鸟苷酸环化酶 (sGC) 激活配体用于 cGMP 合成；然而，NO 和 CO 信号传导的局限性值得研究替代的、病理生理学相关的 cGMP 控制路线。具有挑战性的新发现挑战了 cGMP 发挥作用的传统观念通过 cGMP 依赖性蛋白激酶类型 (cGKI) 发挥血管保护作用，并表明 cGMP 可能通过 cAMP/cAK 发挥作用，促进血管保护。我们实验室目前的研究重点是新型 NO 独立 cGMP 控制方法作为重要的基础科学工具和潜在的心血管疾病疗法。初步数据支持不依赖于 NO 的 cGMP 和表明基质金属蛋白酶 (MMP)-2 和 MMP-9 的机制参与。长期目标该研究项目的目的是研究 VSM 生长的 cGMP 控制策略，以及中央该提议的假设是，不依赖于 NO 的 cGMP 可防止血管生长，并且这通过 cAK 信号发生。将使用两个具体目标来检验这一假设：目标 1 将分析 NO 依赖性 cGMP 和 cGMP 指导的 cGKI/cAK 信号传导在减轻大鼠球囊损伤和小鼠钢丝剥脱损伤模型中的血管重塑。目标 2 将检查基于基质的机制，包括细胞迁移和基质金属蛋白酶平衡大鼠和小鼠原代 VSM 细胞中 cGMP 介导的生长控制。将使用药理学、RNA干扰和病毒基因传递方法，以及有条件的VSM特异性 cGKI 缺陷模型将允许直接比较 cGKI 与 cAK 机制。结果是预计将为不依赖于 NO 的 cGMP 损伤控制提供深入的见解和进一步的证据 VSM 中的生长反应，并揭示了 cGMP 指导的 MMP 在介导这些事件中的作用。心脏和血管的损伤和疾病范围广泛且非常严重的公共卫生问题统计数据显示，它们仍然是美国人口死亡的主要原因。我们相信这些研究的结果将揭示一些新颖且有前途的策略，这些策略可用于最大限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从事基础科学研究和以人为本的临床研究。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Phosphodiesterases Regulate BAY 41-2272-Induced VASP Phosphorylation in Vascular Smooth Muscle Cells.

DOI：
10.3389/fphar.2012.00010
发表时间：
2012
期刊：
Frontiers in pharmacology
影响因子：
5.6
作者：
Adderley SP;Joshi CN;Martin DN;Tulis DA
通讯作者：
Tulis DA

Cyclic Nucleotide-Directed Protein Kinases in Cardiovascular Inflammation and Growth.

DOI：
10.3390/jcdd5010006
发表时间：
2018-01-23
期刊：
Journal of cardiovascular development and disease
影响因子：
2.4
作者：
Holland NA;Francisco JT;Johnson SC;Morgan JS;Dennis TJ;Gadireddy NR;Tulis DA
通讯作者：
Tulis DA

Novel protein kinase targets in vascular smooth muscle therapeutics.

DOI：
10.1016/j.coph.2017.03.003
发表时间：
2017-04
期刊：
Current opinion in pharmacology
影响因子：
4
作者：
Tulis DA
通讯作者：
Tulis DA

Control of vascular smooth muscle cell growth by connexin 43.

DOI：
10.3389/fphys.2012.00220
发表时间：
2012
期刊：
Frontiers in physiology
影响因子：
4
作者：
Joshi CN;Martin DN;Shaver P;Madamanchi C;Muller-Borer BJ;Tulis DA
通讯作者：
Tulis DA

Protease-Activated Receptor 2 Controls Vascular Smooth Muscle Cell Proliferation in Cyclic AMP-Dependent Protein Kinase/Mitogen-Activated Protein Kinase Kinase 1/2-Dependent Manner.

DOI：
10.1159/000532032
发表时间：
2023
期刊：
JOURNAL OF VASCULAR RESEARCH
影响因子：
1.7
作者：
Williams, Madison D.;Bullock, Michael T.;Johnson, Sean C.;Holland, Nathan A.;Vuncannon, Danielle M.;Oswald, Joani Zary;Adderley, Shaquria P.;Tulis, David A.
通讯作者：
Tulis, David A.