Systemic lupus erythematosus (SLE) is a complex autoimmune disease that poses several challenges to the clinician, including heterogeneity of presentation, undulating course, and a significantly elevated risk for vascular dysfunction and premature cardiovascular disease. Traditional risk factors are limited in their ability to discriminate cardiovascular risk in patients with SLE. Platelets, which contain transcripts and the necessary molecular machinery to conduct translation, are intercellular regulators of atherothrombosis, vascular dysfunction, inflammation, and immune activation. Activated platelets can induce endothelial cells and monocytes to produce inflammatory cytokines and chemokines resulting in vascular injury and subsequent atherogenesis. Platelets have been understudied as a relevant contributor to vascular dysfunction and premature cardiovascular disease in SLE. We propose a complementary set of studies to fully evaluate the mechanistic role of platelets in patients with SLE. The array of studies will include platelet activity measurements, coding and non-coding RNA profiles, platelets as effector cells regulating endothelial cell and leukocyte activity in vitro, and measurement of vascular health in vivo using brachial artery reactivity testing. The proposed approach will include a cross sectional study of 200 SLE patients to cover the full spectrum of organ involvement and disease activity. We will also enroll 50 age- sex- and race/ethnicity- matched disease controls. The study hypotheses are that (1) platelet activity measurements and platelet-derived coding and noncoding RNA are significantly influenced by disease activity and clinical phenotype, (2) SLE platelets will induce inflammatory, thrombogenic, and adhesive gene expression and consequent reactivity in endothelial cells, monocytes/macrophages, and vascular smooth muscle cells, and (3) SLE platelet phenotype and transcriptome will significantly associate with impaired vascular function. Longitudinal follow-up in 50 patients representative of both active and quiescent disease will allow us to ascertain whether biologic readouts track with a specific subset of patients and whether the readouts change over time. This study will provide novel data to address existing gaps in knowledge regarding the association between platelet activity measurements, the platelet transcriptome, and platelets as effector cells and vascular health across the clinical spectrum of SLE. This study will ascertain whether there is a unique platelet RNA expression profile in SLE with increased platelet activity and/or with impaired vascular health. Data obtained from this study will identify SLE patients at increased risk for vascular dysfunction and cardiovascular disease by investigating a potentially modifiable risk factor. These data should provide insight into the molecular mechanisms regulating platelet activity in SLE, novel diagnostic tests for risk stratification, and therapeutic targets to improve clinical outcomes.

Public Health Relevance

Systemic lupus erythematosus (SLE) is a remarkably complex disease that poses challenges to the clinician, including heterogeneity of presentation, undulating course, and elevated risk for vascular dysfunction and premature cardiovascular disease. The proposed study will answer the fundamental question of whether platelet activity and the platelet transcriptome are independently associated with vascular health in SLE patients. It is anticipated that understanding differences in platelet activity will improve the ability to identify SLE patients at increased cardiovascular risk and ultimately prevent cardiovascular events.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL139909-01
Application #
9426094
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Charette, Marc F
Project Start
2018-01-01
Project End
2022-11-30
Budget Start
2018-01-01
Budget End
2018-11-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10010