Cardiovascular disease (CVD) is the leading killer of patients with rheumatoid arthritis (RA) who have a 2-3 fold increased risk of myocardial infarction compared to members of the general population. Traditional cardiovascular (CV) risk factors alone do not accurately predict CVD in RA patients and therefore adequate primary prevention strategies are lacking. Systemic inflammation from active RA is strongly associated with CV risk in RA patients, but mechanisms by which inflammation increases CV morbidity and mortality are poorly understood. High density lipoprotein (HDL) is an anti-atherogenic molecule that regulates systemic inflammation by promoting cholesterol efflux and preventing oxidation of low density lipoproteins (LDL). We have previously demonstrated that HDL function is impaired and significantly associated with both disease activity and systemic inflammation, in patients with RA. We further showed that active RA leads to oxidative and protein changes in HDL resulting in dysfunctional HDL. Oxidized low density lipoproteins (ox-LDL) have been directly implicated in the pathogenesis of RA through signaling via the lectin-like ox-LDL receptor 1 (LOX- 1) in the joint synovium. Our preliminary results suggest that modulation of HDL function by increasing HDL's ability to prevent oxidation of LDL is associated with improvement in arthritis activity. We hypothesize that modulation of HDL function represents a novel pathway through which to both decrease arthritis activity and improve CV risk in patients with RA. We will test our hypothesis under two specific aims.
In aim 1, we will evaluate whether modulation of HDL function using HDL mimetic peptides can reduce atherosclerosis and joint inflammation in a recently established mouse model of RA. We will also modulate HDL function by paraoxonase 1 (PON1) gene deletion and overexpression to evaluate the effects on arthritis activity and atherosclerosis in this model.
In aim 2, we will determine whether abnormal HDL function contributes to increased CV risk in a carefully characterized, prospective cohort of over 200 RA patients using in vitro assays of HDL function and targeted HDL proteomics and lipidomics. CV risk will be assessed by the progression of carotid atherosclerosis over three year follow-up and by carotid plaque inflammation using positron emission tomography with fluorodeoxyglucose (FDG-PET). The results of this work may identify important mechanisms through which inflammation increases CV risk in RA patients, and thereby determine new markers for risk assessment and specific targets for intervention.

Public Health Relevance

Cardiovascular disease (CVD) is the leading killer of patients with rheumatoid arthritis (RA). Traditional CV risk factors do not accurately predict CVD in RA patients, and therefore adequate primary prevention strategies are lacking. The current project investigates molecular mechanisms through which inflammation from active RA may predispose patients to CVD, which may identify new markers for risk assessment and specific targets for intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL123064-05
Application #
9607617
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Kirby, Ruth
Project Start
2014-11-15
Project End
2019-10-31
Budget Start
2018-11-01
Budget End
2019-10-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Charles-Schoeman, Christina; Meriwether, David; Lee, Yuen Yin et al. (2018) High levels of oxidized fatty acids in HDL are associated with impaired HDL function in patients with active rheumatoid arthritis. Clin Rheumatol 37:615-622
Charles-Schoeman, C; Gugiu, G B; Ge, H et al. (2018) Remodeling of the HDL proteome with treatment response to abatacept or adalimumab in the AMPLE trial of patients with rheumatoid arthritis. Atherosclerosis 275:107-114
Charles-Schoeman, Christina; Yin Lee, Yuen; Shahbazian, Ani et al. (2017) Improvement of High-Density Lipoprotein Function in Patients With Early Rheumatoid Arthritis Treated With Methotrexate Monotherapy or Combination Therapies in a Randomized Controlled Trial. Arthritis Rheumatol 69:46-57
Bae, Sangmee; Khanlou, Negar; Charles-Schoeman, Christina (2017) Cardiac Transplantation in Dermatomyositis: A case report and literature review. Hum Pathol (N Y) 8:55-58
Charles-Schoeman, Christina; Wang, Xiaoyan; Lee, Yuen Yin et al. (2016) Association of Triple Therapy With Improvement in Cholesterol Profiles Over Two-Year Followup in the Treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheumatol 68:577-86