PROTEOLYSIS OF HMW FGF-2 BY THROMBIN AND ITS CARDIOVASCULAR IMPLICATIONS

凝血酶对 HMW FGF-2 的蛋白水解及其对心血管的影响

基本信息

批准号：
7889211
负责人：
Giuseppe Pintucci
金额：
$ 0.77万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-05 至 2009-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7889211
关键词：
Affect Age Angiogenic Factor Angioplasty Arginine Atherosclerosis Biological Blood Vessels Blood flow Breast Carcinoma C-terminal Cardiovascular Diseases Cardiovascular system Cell Nucleus Cell physiology Cells Cleaved cell Coagulation Process Codon Nucleotides Coronary Arteriosclerosis Country Cultured Cells Cytoplasm Deposition Development Diabetes Mellitus Disease Dyslipidemias Endothelial Cells Endothelium Event Extracellular Matrix Failure Fibroblast Growth Factor Fibroblast Growth Factor 2 Fostering Functional disorder Generations Heart failure Homeostasis Human Hyperplasia Hypertension Impairment In Vitro Inflammation Inflammation Mediators Inflammatory Response Injury Intervention Kidney Failure Lead Malignant Epithelial Cell Matrix Metalloproteinases Mechanics Medial Messenger RNA Methionine Mitogen-Activated Protein Kinases Molecular Molecular Weight Mono-S Morbidity - disease rate N,N-dimethylarginine N-terminal Nitric Oxide Nitric Oxide Synthase Nuclear Oxidants Pathology Patients Peptide Hydrolases Peptides Plasma Platelet-Derived Growth Factor Process Proteins Reaction Role Secondary to Serum Signal Transduction Smooth Muscle Myocytes Source Stress Therapeutic Thrombin Translations Vascular remodeling Veins Western World age related cell motility cell type hypercholesterolemia in vivo inhibitor/antagonist migration mortality novel novel therapeutics outcome forecast prevent tool

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular disease is the major contributor to morbidity and mortality in Western countries. It is characterized by structural and functional changes of blood vessel's wall that lead to reduced blood flow and eventually occlusion. The integrity of the vascular wall is maintained by homeostatic mechanisms controlled by the endothelium. Stress caused by age, oxidants, mechanical injury, and inflammation can result in endothelial dysfunction leading to remodeling of the vessel wall. We found that thrombin, a key protease of the coagulation cascade and inflammatory response, cleaves the high molecular weight (HMW) forms of basic fibroblast growth factor (FGF-2), a ubiquitous protein with trophic effects on vascular cells. The C-terminal fragment of FGF-2 generated by thrombin is similar to low molecular weight (LMW; 18 kDa) FGF-2, and induces vascular cell activation of the mitogen-activated protein kinases ERK-1/2. The N-terminal fragment generated by thrombin cleavage of HMW FGF-2 contains a sequence rich in asymmetric-dimethyl-arginine (ADMA) residues. In free form ADMA inhibits key reactions for blood vessel homeostasis such as nitric oxide synthesis, and its serum levels, elevated in diabetes, renal failure, hypertension, and hypercholesterolemia, correlate with a poor prognosis in cardiovascular patients. We found that thrombin cleavage of HMW FGF-2 dramatically upregulates intracellular ADMA levels in cultured cells. Thus, the C-terminal cleavage product of HMW FGF-2 can activate intracellular signaling and control vascular cell functions, while the N- terminal fragment of FGF-2 generates ADMA, a powerful inhibitor of nitric oxide synthesis. Although degradation of methylarginine-rich proteins is recognized as the major source of free ADMA, the factors controlling this process are unknown. Therefore, we propose to investigate this novel role of FGF-2 in vitro and in vivo. The results of this project can provide relevant information of the pathogenetic mechanisms of vascular injury occurring in hypertension, diabetes, and dyslipidemia, conditions that are all characterized by elevated serum levels of ADMA. The elucidation of these mechanisms will foster the development of new pharmacological tools for the treatment of the cardiovascular disorders associated with these diseases.

描述（由申请人提供）：心血管疾病是西方国家发病率和死亡率的主要因素。它的特征是血管壁的结构和功能变化，导致血液流量减少并最终阻塞。血管壁的完整性由内皮控制的稳态机制维持。年龄，氧化剂，机械损伤和炎症引起的应力会导致内皮功能障碍导致血管壁的重塑。我们发现，凝血酶是凝血级联反应和炎症反应的关键蛋白酶，裂解了基本成纤维细胞生长因子（FGF-2）的高分子量（HMW）形式，这是一种无处不在的蛋白质，对血管细胞有营养作用。凝血酶产生的FGF-2的C末端片段与低分子量（LMW; 18 kDa）FGF-2相似，并诱导有丝分裂原活化蛋白激酶ERK-1/2的血管细胞激活。 HMW FGF-2的凝血酶裂解产生的N末端片段包含富含非对称二甲基 - 精氨酸（ADMA）残基的序列。自由形式，ADMA抑制了血管稳态的关键反应，例如一氧化氮合成及其血清水平，糖尿病，肾衰竭，高血压和高胆固醇血症的升高，与心血管血管病患者的预后不良相关。我们发现，HMW FGF-2的凝血酶切割显着上调培养细胞的细胞内ADMA水平。因此，HMW FGF-2的C末端切割产物可以激活细胞内信号传导和控制血管细胞功能，而FGF-2的N末端片段产生ADMA，这是一种强大的一氧化氮合成抑制剂ADMA。尽管富含甲基氨基氨酸蛋白的降解被认为是自由ADMA的主要来源，但控制该过程的因素尚不清楚。因此，我们建议研究FGF-2在体外和体内的新作用。该项目的结果可以提供有关高血压，糖尿病和血脂异常在血清ADMA水平升高的疾病中的血管损伤致病机制的相关信息。这些机制的阐明将促进开发新的药理学工具来治疗与这些疾病相关的心血管疾病。