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

• 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
• 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

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。炎症损伤和细胞外基质重塑被认为是主要的 血管损伤和动脉僵硬的病理原因。然而，启动的分子机制 以及在大血管中传播与衰老相关的病理变化仍不清楚。在此，我们建议 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， 肥胖和非肥胖老年小鼠的炎症和纤维化。中性粒细胞数量最多 白细胞的寿命很短，在引发组织损伤和炎症方面发挥着关键作用。我们的数据 证明（1）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 与衰老相关的主动脉炎症、纤维化和钙化。我们还观察到 NE 具有强大的作用 增加血管内皮通透性和增强主动脉平滑肌细胞纤维化 成骨表型转换。此外，NE 通过降解中性粒细胞促炎表型来调节 长寿调节因子 Sirtuin 1 (Sirt1)。根据我们的初步数据，我们假设促炎症 中性粒细胞与血管相互作用，通过释放 NE 引起血管损伤和重塑。 后者有助于增加血管通透性、血液中的纤维化重塑和钙化 船只。因此，抑制 NE 可能会对衰老相关的血管损伤、纤维化重塑、 钙化，以及随后的动脉僵硬。该 RO1 提案的目的是探索中性粒细胞如何 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 致肥胖的饮食。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 血管平滑肌细胞的体外和体内研究。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 老鼠。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 小鼠僵硬。该项目的成功完成将为血管衰老提供一种新颖的治疗策略 及相关疾病。