763 - Oxidation Products of Arachidonic Acid and Linoleic Acid Are Increased in High Density Lipoprotein and Low Density Lipoprotein From Patients with Active Rheumatoid Arthritis

Sunday, November 6, 2011: 3:30 PM
W375a (McCormick Place West)
Christina Charles-Schoeman1, David Meriwether2, Yuen Yin Lee2 and Srinivasa T. Reddy3, 1UCLA David Geffen School of Medicine, Los Angeles, CA, 2UCLA, Los Angeles, CA, 3UCLA, Los Angeles
Presentation Number: 763

Background/Purpose: Oxidation products of arachidonic acid and linoleic acid including hydroxyeicosatetraenoic acids (HETES) and hydroxyoctadecadienoic acids (HODES), respectively, play an important role in the pathogenesis of atherosclerosis.  These fatty acids contribute to the oxidation of low density lipoprotein (LDL) and their accumulation in high density lipoprotein (HDL) has been proposed to inhibit HDL function, increasing atherosclerotic risk.  The current work evaluated the levels of HETES and HODES in HDL and LDL isolated from patients with active rheumatoid arthritis (RA) compared to healthy controls.

Methods: HDL and LDL were isolated from plasma using fast protein liquid chromatography for 10 RA patients and 8 age and sex matched healthy controls. 5-HETE, 12-HETE, 15-HETE, 9-HODE, and 13-HODE levels in HDL and LDL fractions were measured by mass spectrometry as described previously (Imaizumi et al. Drug Metab Lett. 2010; 4(3):139-48). HDL's anti-inflammatory function was measured by a cell free assay as described previously (Charles-Schoeman et al. Arthritis Rheum. 2009; 60(10):2870-9). Lipoprotein cholesterol levels were determined by standard methods.

 

Results: 5-HETE, 15-HETE, 9-HODE and 13-HODE levels were significantly increased in both HDL and LDL isolated from patients with active RA compared to healthy controls (see Table). The levels of oxidized fatty acids in HDL correlated significantly with measures of systemic inflammation; ESR and hs-CRP (r values= 0.70-0.80, [ESR]; 0.65-0.74 [hs-CRP]; p values <0.004).  Similar correlations were also noted for oxidized fatty acids in LDL (r values= 0.30-0.48, [ESR]; 0.34-0.62 [HSCRP]; p values 0.006-0.25).  Moreover, 5-HETE, 15-HETE, 9-HODE and 13-HODE levels in HDL significantly correlated with impaired HDL function as measured by the HDL inflammatory index (HII), r= 0.54-0.58; p values <0.03).  No differences in lipoprotein cholesterol levels or traditional cardiovascular risk factors were noted between the two groups.

 

Conclusions:  Oxidation products of arachidonic acid and linoleic acid are increased in HDL and LDL from patients with active rheumatoid arthritis compared to healthy controls, and are strongly correlated with levels of systemic inflammation, particularly in HDL.  Elevations of 5-HETE, 15-HETE, 9-HODE and 13-HODE in HDL are also significantly associated with impaired HDL anti-oxidant function.  These results suggest a potential mechanism by which active inflammation from RA increases oxidized fatty acids in circulating lipoproteins, promoting LDL oxidation and HDL dysfunction, thereby increasing atherosclerotic risk. Further investigation of therapeutic agents such as apoA-1 mimetic peptides which bind oxidized fatty acids and reduce atherosclerosis in animal models may be warranted in patients with RA.

 

 

Rheumatoid Arthritis (n=10)

Healthy Control (n=8)

Age (years)

49.6 ± 11.8 

48.4 ± 15.9

Sex (% female)

80% 

75%

Ethnicity (% caucasian)

80% 

63%

Total Cholesterol (mg/dL)

178 ± 52   

165 ± 22

LDL Cholesterol (mg/dL)

104 ± 35  

89 ± 22

HDL Cholesterol (mg/dL)

52 ± 15  

56 ± 14

Triglycerides (mg/dL)

116 ± 59

101 ± 84

ESR  (mm/hr)

71 ± 24*    

6 ± 5

HS-CRP (mg/L)

42.1 ± 40.1*    

0.91 ± 1.5

HDL Inflammatory Index (HII)

2.21 ± 0.52*   

0.56 ± 0.09

HDL 5-HETE (ng/ml)

72.1 ± 29.1*   

29.2 ± 13.2

HDL 12-HETE (ng/ml)

779.4 ± 1693  

166.7  ± 40

HDL 15-HETE (ng/ml)

18.9 ± 10.9*   

7.0 ± 2.5

HDL 9-HODE (ng/ml)

138.4 ± 74.2*

47.6 ± 28.5

HDL 13-HODE (ng/ml)

190.9 ± 99.5* 

68.4  ± 30.7

LDL 5-HETE (ng/ml)

2.9 ± 1.4*   

1.1 ± 0.7

LDL 12-HETE (ng/ml)

38.1 ± 47.7  

16.9 ± 15.7

LDL 15-HETE (ng/ml)

2.35 ± 0.85*   

1.06 ± 0.72

LDL 9-HODE (ng/ml)

26.5 ± 18.0* 

 8.8 ± 7.2

LDL 13-HODE (ng/ml)

34.0 ± 22.4* 

11.3 ± 8.0

All values mean ± standard deviation.  *p value ≤ 0.005 compared to controls.

 

 

 


Keywords: atherosclerosis, cholesterol and rheumatoid arthritis (RA)

Disclosure: C. Charles-Schoeman, None; D. Meriwether, None; Y. Y. Lee, None; S. T. Reddy, None.