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Novel mechanisms of the thrombotic complications of atherosclerosis

动脉粥样硬化血栓并发症的新机制

基本信息

批准号：
10428552
负责人：
Peter Libby
金额：
$ 42.1万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10428552
关键词：
Arginine deiminase Arterial Fatty Streak Arteries Atherosclerosis Attenuated Biological Clinic Clinical Clinical Data Collagen Collection Coronary artery Data Disease Endothelium Event Glycosaminoglycans Hematopoiesis Human Individual Injury Insulin Resistance Intervention Knowledge Lesion Link Lipids Low-Density Lipoproteins Marshal Medical Metabolic syndrome Molecular Molecular Probes Mus Myelogenous Myeloid Cells Myocardial Infarction Obesity Pathologic Patients Preparation Process Proteins Proteoglycan Publishing Research Risk Risk Factors Role Rupture Site Somatic Mutation Testing Thinness Thrombosis Ursidae Family Variant Work Yawning acute coronary syndrome atherosclerosis risk atherothrombosis cardiovascular risk factor demographics experimental study extracellular granulocyte improved in vivo in vivo evaluation inhibitor interstitial macrophage neutrophil novel novel therapeutic intervention pre-clinical profiles in patients thrombotic thrombotic complications young woman

项目摘要

Current clinical and pathological data suggest an ongoing major shift in the mechanisms of the thrombotic complications of human atherosclerosis. Human plaques contain less lipid and fewer macrophages in the statin era. Patients with acute coronary syndromes (ACS) include more and younger women, and obese and insulin resistant individuals. ST segment elevation myocardial infarctions (STEMIs) have declined as non-STEMIs have risen. We have marshaled evidence for a shift in the mechanisms of ACS. In the current era of intense LDL lowering, rupture of so-called “vulnerable plaques” now causes fewer acute coronary syndromes while superficial erosion is increasing as a proportion of ACS. While we have considerable mastery of the biological basis of plaque rupture, and the mechanisms by which lipid- lowering can attenuate this trigger of thrombosis, a striking knowledge gap yawns regarding mechanisms of superficial erosion. This process differs substantially from plaque rupture: human lesions that have provoked erosion generally lack a prominent lipid collection, have few macrophages and more proteoglycan and glycosaminoglycans (GAGs) rather than thin, collagen-poor fibrous caps. Recent clinical data suggest that the management ACS due to erosion, unlike those due to plaque rupture, does not require urgent invasive treatment, rendering the quest for greater understanding of the mechanisms of erosion medically imperative. Our newly published data suggest a role for neutrophils (polymorphonuclear leukocytes, PMN), and neutrophil extracellular traps (NETs) in superficial erosion. We will use a validated experimental preparation in mice that superimposes disturbed flow on a GAG and proteoglycan-rich intima, conditions that pertain to human plaques complicated by superficial erosion, to probe molecular and cellular mechanisms of this type of thrombotic complication of atherosclerosis. My proposal centers on the unified theme of PMN and NET functions. 1) We will test using mice deficient in peptidyl arginine deiminase 4 (PAD4) the hypothesis that at sites of flow disturbance in arteries with erosion-like intimas, NETs participate critically in local endothelial injury and thrombosis. 2) We will test the hypothesis that myeloid-related protein (MRP) 8/14, we have previously implicated in arterial diseases, contributes to local NETosis and in endothelial injury and thrombosis at sites of flow disturbance in arteries with erosion-like intimas. 3) We test the hypothesis that mice bearing in myeloid cells the V617F Jak2 variant associated with clonal hematopoiesis and increased atherosclerotic risk in humans, will have aggravated NETosis and endothelial injury and thrombosis at sites of flow disturbance in arteries with erosion-like intimas. This aim will not only provide mechanistic information regarding superficial erosion, but will help elucidate the mechanism of increased thrombotic events in individuals who bear this somatic mutation common in those with clonal hematopoiesis, a newly recognized potent cardiovascular risk factor. Our studies will also explore novel therapeutic strategies immediately translatable to the clinic.

目前的临床和病理数据表明，该疾病的机制正在发生重大转变

项目成果

期刊论文数量（43）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

IL-6 helps weave the inflammatory web during acute coronary syndromes.

DOI：
10.1172/jci167670
发表时间：
2023-06-01
期刊：
JOURNAL OF CLINICAL INVESTIGATION
影响因子：
15.9
作者：
Nakao, Tetsushi;Libby, Peter
通讯作者：
Libby, Peter

Targeting Inflammatory Pathways in Cardiovascular Disease: The Inflammasome, Interleukin-1, Interleukin-6 and Beyond.

DOI：
10.3390/cells10040951
发表时间：
2021-04-20
期刊：
Cells
影响因子：
6
作者：
Libby P
通讯作者：
Libby P

Inflammation and Cholesterol as Predictors of Cardiovascular Events Among 13 970 Contemporary High-Risk Patients With Statin Intolerance.

DOI：
10.1161/circulationaha.123.066213
发表时间：
2024-01-02
期刊：
CIRCULATION
影响因子：
37.8
作者：
Ridker, Paul M.;Lei, Lei;Louie, Michael J.;Haddad, Tariq;Nicholls, Stephen J.;Lincoff, A. Michael;Libby, Peter;Nissen, Steven E.
通讯作者：
Nissen, Steven E.

EPA and DHA containing phospholipids have contrasting effects on membrane structure.