Session Title: Rheumatoid Arthritis - Animal Models
Session Type: Abstract Submissions (ACR)
Patients with rheumatoid arthritis (RA) have significantly increased cardiovascular (CV) morbidity and mortality. Abnormal function of high density lipoprotein (HDL) has been implicated as a mechanism for this increased CV risk. The current work investigated HDL function in the K/BxN mouse model of RA.
Male KRN mice were crossed with NOD female mice expressing the MHC class II molecule Ag7 to generate K/BxN mice. 29 mice were assessed for arthritis activity using caliper measurements of hindlimbs and clinical scores 3 times weekly until sacrifice/serum collection at 21 weeks. HDL function was assessed by a previously published cell free assay (A&R 2009; 60: 2870) and paraoxonase 1 (PON1) activity was assessed using both paraoxon and dihydrocumarin as substrates (A&R2013; 65: 2765). Total and HDL cholesterol (HDL-C) were assessed by standard assays.
Greater arthritis activity measured by higher hind limb scores in K/BxN mice was significantly associated with decreased ability of HDL to inhibit LDL oxidation (higher HDL inflammatory index (HII)); r = 0.5, p=0.01 for correlation of hind limb scores with HII at 21 weeks), and decreased PON1 activity measured using both paraoxon and dihydrocumarin as substrates ( r = -0.6, p=0.0001 and r = -0.7, p<0.0001 respectively). Higher arthritis activity in K/BxN mice (hind limb scores) was also associated with greater suppression of total cholesterol (TC) and HDL-C, (r values = -0.6, p values =0.001). A marked correlation was observed between the suppression of HDL-C levels and impairment in HDL function (r = -0.8 for correlation of HDL-C with HII, p<0.0001).
Inflammatory arthritis in K/BxN mice is associated with suppression of HDL- C levels and the generation of more pro-inflammatory, dysfunctional HDL particles. These results are consistent with our prior work showing an association of higher disease activity in RA patients with worse HDL function. This model will be used for further evaluation of mechanisms linking abnormal HDL function to CV risk in RA.
Y. Y. Lee,
S. T. Reddy,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inflammatory-arthritis-in-kbxn-mice-is-associated-with-abnormal-hdl-function/