Role of inflammation in intraplaque hemorrhage pathogenesis
炎症在斑块内出血发病机制中的作用
基本信息
- 批准号:10615058
- 负责人:
- 金额:$ 80.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAccelerationAchievementAddressAffectAntibodiesArterial Fatty StreakAtherosclerosisB-LymphocytesBlood VesselsCardiovascular systemCarotid Artery PlaquesCarotid EndarterectomyCause of DeathCell SeparationCellsCholesterolClinicalCoculture TechniquesCollaborationsComplementDataDevelopmentElementsEndothelial CellsEndotheliumErythrocytesEventExcisionFollow-Up StudiesGoalsGrowthGuidelinesHealth Care CostsHemoglobinHemorrhageHistologicHistologyHumanHypoxiaImageImaging TechniquesImmunoglobulin MIn VitroInflammationInflammatoryInvestigationIschemiaKnowledgeLipidsLow-Density LipoproteinsMacrophageMagnetic Resonance ImagingMeasuresMyocardial InfarctionNecrosisOxygenPathogenesisPathologyPatientsPermeabilityPersonsPlasmaProductionQuality of lifeResidual stateRiskRoleScanningSourceSpecimenStrokeTestingTissuesTunica AdventitiaUnited StatesVascular DiseasesVascular Permeabilitiesatheroprotectiveblood pressure controlcardiovascular disorder riskcontrast enhancedcoronary plaquedensitydriving forcefollow-uphistological studiesin vivoinhibitor therapyneovascularizationneovasculaturenovelnovel therapeutic interventionpreventresponsetherapeutic targettreatment responsevasa vasorum
项目摘要
PROJECT SUMMARY
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death in the US. Despite
guidelines promoting aggressive anti-atherosclerotic therapies, there is »5%/year residual ASCVD risk in
patients who achieve profound LDL-C lowering (median 30 mg/dL) with combined statin and PCSK9 inhibitor
therapy. New treatment strategies are needed to target the mechanisms beyond LDL to reduce this residual
risk. Histologic studies have demonstrated that plaque neovasculature constitutes the main entrance for
inflammatory cells into plaques and provides a major source for the formation and progression of intraplaque
hemorrhage (IPH). IPH, mainly resulting from plaque neovascularization, is a common feature of advanced
atherosclerotic lesions and a critical element leading to accelerated plaque progression, plaque instability and
ischemic vascular events in humans. We found that plaque neovessel permeability (measured as Ktrans, using
dynamic contrast enhanced magnetic resonance imaging) is strongly correlated with macrophage content and
that greater adventitial Ktrans is associated with IPH. Recent studies have identified that CD163+ macrophages
are associated with IPH and can further promote neovascularization leading to IPH progression. On the other
hand, B1 cell-derived IgM can inhibit inflammation and reduce atherosclerosis, and circulating human B1 cells
are inversely associated with coronary plaque volume and instability features. Our preliminary data showed
that plasma IgM levels are reduced in patients with carotid IPH and B1 cells are inversely associated with IPH
progression. We, therefore, propose to study the role of B1 cell-derived IgM and B1 cells in IPH pathology.
To test a novel hypothesis that B1 cell-derived IgM levels are reduced in patients with IPH and that
the reduction in protective IgMs results in unobstructed IPH-promoted inflammation and neovessel
permeability, thereby exacerbating plaque progression, we propose to conduct comprehensive studies
including: (1) histological examination of CEA specimens to determine whether plaques with increased Ktrans
and/or IPH have a lower density of IgM and a higher density of CD163+ macrophages; (2) a longitudinal clinical
follow-up study in 250 patients to determine whether lower IgM levels and B1 cells predict progression of Ktrans
and IPH and whether IgM production and effect on macrophages are different in B1 cells in patients with and
without IPH; (3) in vitro mechanistic studies of endothelial sprouting and leakiness using 3D microvessels to
determine the effects of IgM and B1 cells on RBC-induced changes in macrophages and vascular permeability.
This proposal utilizes state-of-the-art imaging technique for quantification of vascular permeability and IPH
and 3D microvessels for study how hemoglobin-stimulated macrophages and B1 cells and/or IgM influence
endothelial function related vascular permeability. Our study will gain new knowledge to uncover inflammatory
mechanisms in IPH pathogenesis and to discover potential therapeutic targets with a goal of reduced vascular
permeability to prevent IPH and its progression, which will ultimately reduce residual ASCVD risk.
项目概要
动脉粥样硬化性心血管疾病(ASCVD)仍然是美国的首要死因。尽管
促进积极抗动脉粥样硬化治疗的指南中,每年有 5% 的残余 ASCVD 风险
使用他汀类药物和 PCSK9 抑制剂联合治疗实现深度 LDL-C 降低(中位 30 mg/dL)的患者
治疗。需要新的治疗策略来针对 LDL 以外的机制,以减少这种残留
风险。组织学研究表明,斑块新生血管构成了主要入口
炎症细胞进入斑块并为斑块内形成和进展提供主要来源
出血(IPH)。 IPH,主要由斑块新生血管形成引起,是晚期疾病的共同特征
动脉粥样硬化病变是导致斑块加速进展、斑块不稳定和
人类缺血性血管事件。我们发现斑块新生血管通透性(以 Ktrans 测量,使用
动态对比增强磁共振成像)与巨噬细胞含量密切相关,
更大的外膜 Ktrans 与 IPH 相关。最近的研究发现 CD163+ 巨噬细胞
与 IPH 相关,可进一步促进新生血管形成,导致 IPH 进展。另一方面
另一方面,B1细胞衍生的IgM可以抑制炎症并减少动脉粥样硬化,并且循环人类B1细胞
与冠状动脉斑块体积和不稳定特征呈负相关。我们的初步数据显示
颈动脉 IPH 患者血浆 IgM 水平降低,B1 细胞与 IPH 呈负相关
进展。因此,我们建议研究 B1 细胞来源的 IgM 和 B1 细胞在 IPH 病理学中的作用。
检验一项新假设,即 IPH 患者中 B1 细胞衍生的 IgM 水平降低,并且
保护性 IgM 的减少导致 IPH 促进的炎症和新生血管畅通无阻
渗透性,从而加剧斑块进展,我们建议进行全面的研究
包括:(1)CEA标本的组织学检查以确定是否有Ktrans增加的斑块
和/或IPH具有较低密度的IgM和较高密度的CD163+巨噬细胞; (2)纵向临床
对 250 名患者进行的后续研究,以确定较低的 IgM 水平和 B1 细胞是否可以预测 Ktrans 的进展
和 IPH 以及 IgM 产生和对巨噬细胞的影响是否在 IPH 和 IPH 患者的 B1 细胞中不同
没有 IPH; (3) 使用 3D 微血管进行内皮出芽和渗漏的体外机制研究
确定 IgM 和 B1 细胞对红细胞诱导的巨噬细胞和血管通透性变化的影响。
该提案利用最先进的成像技术来量化血管通透性和 IPH
和 3D 微血管,用于研究血红蛋白刺激的巨噬细胞和 B1 细胞和/或 IgM 如何影响
内皮功能相关的血管通透性。我们的研究将获得新的知识来揭示炎症
IPH 发病机制,并发现潜在的治疗靶点,以减少血管
渗透性以预防 IPH 及其进展,最终降低残余 ASCVD 风险。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jenny E. Kanter其他文献
Apolipoprotein C3 induces inflammasome activation only in its delipidated form
载脂蛋白 C3 仅在其去脂形式下诱导炎性小体激活
- DOI:
10.1038/s41590-023-01423-2 - 发表时间:
2023-02-13 - 期刊:
- 影响因子:27.600
- 作者:
Cheng-Chieh Hsu;Baohai Shao;Jenny E. Kanter;Yi He;Tomas Vaisar;Joseph L. Witztum;Janet Snell-Bergeon;Gregory McInnes;Shannon Bruse;Omri Gottesman;Adam E. Mullick;Karin E. Bornfeldt - 通讯作者:
Karin E. Bornfeldt
Effect of complete, lifelong ANGPTL3 deficiency on triglyceride-rich lipoprotein kinetics
完全、终生 ANGPTL3 缺乏对富含甘油三酯脂蛋白动力学的影响
- DOI:
10.1016/j.xcrm.2025.102152 - 发表时间:
2025-06-17 - 期刊:
- 影响因子:10.600
- 作者:
Alan Fappi;Bruce W. Patterson;Kendal H. Burks;Nicholas O. Davidson;Tomas Vaisar;Jenny E. Kanter;Karin E. Bornfeldt;Edward A. Fisher;Ira J. Goldberg;Nathan O. Stitziel;Bettina Mittendorfer - 通讯作者:
Bettina Mittendorfer
Type I IFN induces long-chain acyl-CoA synthetase 1 to generate a phosphatidic acid reservoir for lipotoxic saturated fatty acids
I 型干扰素诱导长链酰基辅酶 A 合成酶 1 产生用于脂毒性饱和脂肪酸的磷脂酸储存库
- DOI:
10.1016/j.jlr.2024.100730 - 发表时间:
2025-01-01 - 期刊:
- 影响因子:4.100
- 作者:
Shelley Barnhart;Masami Shimizu-Albergine;Eyal Kedar;Vishal Kothari;Baohai Shao;Melissa Krueger;Cheng-Chieh Hsu;Jingjing Tang;Jenny E. Kanter;Farah Kramer;Danijel Djukovic;Vadim Pascua;Yueh-Ming Loo;Lucrezia Colonna;Sadie J. Van den Bogaerde;Jie An;Michael Gale;Karen Reue;Edward A. Fisher;Sina A. Gharib;Karin E. Bornfeldt - 通讯作者:
Karin E. Bornfeldt
Small HDL, diabetes, and proinflammatory effects in macrophages
小 HDL、糖尿病和巨噬细胞的促炎作用
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
V. Kothari;Yi He;Farah Kramer;Shelley Barnhart;Jenny E. Kanter;Jingjing Tang;Jeremy Frey;T. Vaisar;J. Heinecke;K. Bornfeldt - 通讯作者:
K. Bornfeldt
Inflammatory stimuli induce acyl-CoA thioesterase 7 and remodeling of phospholipids containing unsaturated long (≥C20)-acyl chains in macrophages[S]
炎症刺激诱导酰基辅酶A硫酯酶7和巨噬细胞中含有不饱和长(≥C20)酰基链的磷脂的重塑[S]
- DOI:
- 发表时间:
2017 - 期刊:
- 影响因子:6.5
- 作者:
Valerie Z. Wall;Shelley Barnhart;Farah Kramer;Jenny E. Kanter;Anuradha Vivekanandan;S. Pennathur;C. Bolego;J. Ellis;M. Gijon;M. Wolfgang;K. Bornfeldt - 通讯作者:
K. Bornfeldt
Jenny E. Kanter的其他文献
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{{ truncateString('Jenny E. Kanter', 18)}}的其他基金
APOC3 mediated dyslipidemia in diabetic kidney disease and atherosclerosis
APOC3 介导的糖尿病肾病和动脉粥样硬化中的血脂异常
- 批准号:
10580375 - 财政年份:2022
- 资助金额:
$ 80.77万 - 项目类别:
Role of inflammation in intraplaque hemorrhage pathogenesis
炎症在斑块内出血发病机制中的作用
- 批准号:
10392657 - 财政年份:2022
- 资助金额:
$ 80.77万 - 项目类别:
APOC3 mediated dyslipidemia in diabetic kidney disease and atherosclerosis
APOC3 介导的糖尿病肾病和动脉粥样硬化中的血脂异常
- 批准号:
10337327 - 财政年份:2020
- 资助金额:
$ 80.77万 - 项目类别:
Core C: Myeloid cell and atherosclerosis core
核心C:骨髓细胞和动脉粥样硬化核心
- 批准号:
10450860 - 财政年份:2020
- 资助金额:
$ 80.77万 - 项目类别:
Core C: Myeloid cell and atherosclerosis core
核心C:骨髓细胞和动脉粥样硬化核心
- 批准号:
10642743 - 财政年份:2020
- 资助金额:
$ 80.77万 - 项目类别:
APOC3 mediated dyslipidemia in diabetic kidney disease and atherosclerosis
APOC3 介导的糖尿病肾病和动脉粥样硬化中的血脂异常
- 批准号:
10713362 - 财政年份:2020
- 资助金额:
$ 80.77万 - 项目类别:
APOC3 mediated dyslipidemia in diabetic kidney disease and atherosclerosis
APOC3 介导的糖尿病肾病和动脉粥样硬化中的血脂异常
- 批准号:
10557149 - 财政年份:2020
- 资助金额:
$ 80.77万 - 项目类别:
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