Neutrophils play a pivotal role in vascular aging

中性粒细胞在血管老化中发挥关键作用

基本信息

批准号：
10637703
负责人：
Zhen Yue Jiang
金额：
$ 58.34万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-22 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10637703
关键词：
Acetylation Aging Amiloride Animals Aorta B-Lymphocytes BMP2 gene Blood Pressure Blood Vessels C57BL/6 Mouse CXC Chemokines Cardiovascular Diseases Cell Adhesion Molecules Cells Chronic Cytoplasmic Granules DNA Binding Data Deacetylase Development Diet Disease Elastases Endothelium Event Extracellular Matrix Extravasation Fatty acid glycerol esters Female Fibrosis Fructose Human Immune In Vitro Infiltration Inflammation Inflammatory Injury Knock-out Knockout Mice Leucocytic infiltrate Leukocyte Elastase Leukocytes Longevity MADH2 gene Measures Medial Mediating Mediator Molecular Mus Neutrophil Infiltration Nuclear Translocation Obesity Oral Oxidants PAR-2 Receptor Pathologic Pathway interactions Peptide Hydrolases Permeability Phenotype Phosphotransferases Physiologic pulse Play Prevalence Process Production Regulation Reporting Resistance Role SIRT1 gene Serine Protease Signal Pathway Signal Transduction Site Smooth Muscle Smooth Muscle Myocytes Testing Therapeutic Effect Tissues Transforming Growth Factor beta Vascular Dementia Vascular Endothelial Cell Vascular Endothelium Vascular Permeabilities Vascular Smooth Muscle Vascular remodeling age related aged arterial stiffness calcification chemokine receptor connective tissue growth factor epithelial Na+ channel feeding in vivo male migration mouse model neutrophil neutrophil elastase inhibitor novel novel therapeutic intervention obesogenic osteogenic progenitor protective effect tissue injury vascular endothelium permeability vascular injury

项目摘要

Abstract Arterial stiffness is a hallmark of vascular aging and is related to increased cardiovascular disease events and vascular dementias. Inflammatory damage and extracellular matrix remodeling have been proposed as the major pathological causes of vascular injury and arterial stiffness. However, the molecular mechanisms that initiate and propagate aging-related pathological changes in large blood vessels remain unclear. Here, we propose to study the role of neutrophil elastase (NE), a neutrophil-specific protease, in initiating vascular leakage, inflammation and fibrosis in aged mice both with and without obesity. Neutrophils are the most abundant leukocytes, have a short lifespan, and play a critical role in initiating tissue damage and inflammation. Our data demonstrated (1) that pulse wave velocity (PWV), the primary parameter of arterial stiffness, was decreased in NE knockout (NEKO) mice compared to their wild-type littermates, and (2) that NEKO mice were resistant to aging-related inflammation, fibrosis and calcification in the aorta. We also observed that NE has potent effects on increasing vascular endothelial permeability and enhancing aortic smooth muscle cell fibrogenic and osteogenic phenotypic switch. Further, NE regulates neutrophil proinflammatory phenotype by degrading longevity regulator Sirtuin 1 (Sirt1). Based on our preliminary data, we hypothesize that pro-inflammatory neutrophils interact with blood vessels, causing vascular damage and remodeling through the release of NE. The latter contributes to the increased vascular permeability, fibrotic remodeling and calcification in the blood vessels. Thus, inhibiting NE may lead to protective effects on aging-related vascular damage, fibrotic remodeling, calcification, and subsequent arterial stiffness. The objective of this RO1 proposal is to explore how neutrophils and NE regulate inflammatory remodeling in the arterial wall during the aging process with or without feeding of an obesogenic diet. We will explore whether NE contributes to vascular aging by activating protease-activated receptor 2 (PAR2) and epithelium sodium channel (ENaC) signaling pathways in vascular endothelial cells and vascular smooth muscle cells with both in vitro and in vivo studies. Also, we will examine the role of the NE–Sirt1 signaling pathway in the regulation of neutrophil phenotype and aging-related vascular injury and remodeling in mice. Finally, we will evaluate potential therapeutic effects of a selective NE inhibitor on aging-related arterial stiffness in mice. Successful completion of this project will provide a novel therapeutic strategy for vascular aging and related diseases.

抽象的动脉僵化是血管老化的标志，与心血管疾病事件的增加和血管性痴呆被认为是主要的炎症损伤和细胞外基质重塑。然而，血管损伤和动脉僵化的病理原因是启动的分子机制。和在大血管中传播与衰老相关的病理变化仍不清楚。研究中性粒细胞弹性蛋白酶（NE）（一种中性粒细胞特异性蛋白酶）在引发血管渗漏中的作用，肥胖和未肥胖的老年小鼠的炎症和纤维化最为丰富。我们的数据显示，白细胞的寿命很短，并且在引发组织损伤和炎症方面发挥着关键作用。 (1) 证明脉搏波速度 (PWV)（动脉僵硬度的主要参数）在 NE 敲除 (NEKO) 小鼠与其野生型同窝小鼠相比，以及 (2) NEKO 小鼠对我们还观察到 NE 对主动脉中与衰老相关的炎症、纤维化和钙化具有有效作用。增加血管内皮通透性和增强主动脉平滑肌细胞纤维化此外，NE 通过降解调节中性粒细胞促炎表型。根据我们的初步数据，我们捕获了长寿调节因子 Sirtuin 1 (Sirt1)。中性粒细胞与血管相互作用，通过释放 NE 造成血管损伤和重塑。后者有助于增加血管通透性、血液中的纤维化重塑和钙化因此，抑制 NE 可能会对衰老相关的血管损伤、纤维化重塑产生保护作用。 RO1 提案的目的是探索中性粒细胞如何发生钙化和随后的动脉硬化。 NE 和 NE 在衰老过程中调节动脉壁的炎症重塑，无论是否进食我们将探讨 NE 是否通过激活蛋白酶激活而导致血管老化。血管内皮细胞中的受体 2 (PAR2) 和上皮钠通道 (ENaC) 信号通路此外，我们还将研究 NE-Sirt1 的作用。中性粒细胞表型调节及衰老相关血管损伤和重塑的信号通路最后，我们将评估选择性 NE 抑制剂对衰老相关动脉的潜在治疗效果。该项目的成功完成将为血管老化提供一种新的治疗策略。及相关疾病。