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.

抽象的动脉僵硬是血管衰老的标志，与心血管疾病事件的增加有关和血管痴呆。已经提出了炎症损伤和细胞外基质重塑作为主要血管损伤和动脉僵硬的病理原因。但是，启动的分子机制大型血管中与衰老相关的病理变化尚不清楚。在这里，我们建议研究中性粒细胞特异性蛋白酶的中性粒细胞弹性酶（NE）在启动血管渗漏中的作用，有或没有肥胖症的老年小鼠的炎症和纤维化。中性粒细胞是最丰富的白细胞的寿命短，在开始的组织损伤和炎症中起着至关重要的作用。我们的数据证明（1）脉冲波速度（PWV）是动脉刚度的主要参数，在与野生型窝窝相比，NE敲除（Neko）小鼠，（2）Neko小鼠对主动脉中与衰老相关的炎症，纤维化和钙化。我们还观察到NE具有潜在的影响增加血管内皮渗透性并增强主动脉平滑肌细胞纤维纤维化和成骨表型开关。此外，NE通过退化来调节中性粒细胞促炎表型长寿调节器Sirtuin 1（SIRT1）。根据我们的初步数据，我们假设这种促炎性中性粒细胞与血管相互作用，通过释放NE引起血管损伤并重塑。后来有助于血管通透性增加，血液中的纤维化重塑和钙化船只。这是抑制NE可能会导致对与衰老相关的血管损伤，纤维化重塑的保护作用，钙化和随后的动脉刚度。该RO1建议的目的是探索中性粒细胞在老化过程中，NE调节动脉壁中的炎症重塑，或者不进食肥胖饮食。我们将探索NE是否通过激活蛋白酶激活而导致血管衰老血管内皮细胞和血管内皮细胞中的受体2（PAR2）和上皮钠通道（ENAC）信号通路具有体外和体内研究的血管平滑肌细胞。此外，我们将研究NE – Sirt1的作用中性粒细胞表型和与衰老相关的血管损伤和重塑中的信号通路老鼠。最后，我们将评估选择性NE抑制剂对与衰老相关的动脉的潜在治疗作用小鼠的刚度。该项目的成功完成将为血管衰老提供新颖的热策略和相关疾病。