25Interleukin-1 receptor-associated kinase-3 plays a crucial role in rosiglitazone-mediated reduction of atherosclerotic plaque macrophages

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Abstract

Purpose

Synthetic peroxisome proliferator-activated receptor (PPAR) agonists are used to treat dyslipidemia and insulin resistance. Recent data also suggest critical roles of PPAR agonists in inhibiting vascular inflammation and atherosclerosis. However, the molecular mechanisms that confer their vascular protection are poorly understood. In this study, we examined molecular mechanisms that explain differential effects of a PPARalpha agonist (fenofibrate) and a PPARgamma agonist (rosiglitazone) on macrophages during obesity-induced atherogenesis.

Methods and Results

Twelve-week-old mice with combined leptin and LDL-receptor deficiency, a model for the metabolic syndrome and atherosclerosis, were treated with fenofibrate (50 mg kg−1 day−1, n=14), rosiglitazone (10 mg kg−1 day−1, n=13) or placebo (n=26) for 12 weeks. Rosiglitazone in contrast to fenofibrate lowered systemic inflammation evidenced by lower levels of TNFalpha and IL-6, and restored insulin sensitivity evidenced by a decrease in homeostasis model of assessment (HOMA) index and decreased atherogenesis as determined by immunohistochemistry. Furthermore, rosiglitazone and not fenofibrate increased blood adiponectin levels, and decreased both monocyte chemoattractant protein-1 (Mcp1) abundance and M1 polarization in adipose tissue and atherosclerotic plaques. The inhibition of phenotypic switch to M1-polarized macrophages by rosiglitazone was associated with increased interleukin-1 receptor-associated kinase-3 (Irak3) expression. Irak3, a kinase-deficient member of the Irak family, is exclusively expressed in monocytes/macrophages and is an important negative regulator of Toll-like receptor signalling. In bone marrow-derived macrophages (BMDM, n=6), fenofibrate, in contrast to rosiglitazone, increased the M1 polarization and both PPAR agonists decreased the Mcp1 expression. Interestingly, the rosiglitazone-associated increase in Irak3 (RNA and protein), induced by high levels of adiponectin (10 μg/mL), was required for the decrease in Mcp1 as observed in Irak3-/- BMDM. P < 0.05 was considered statistically significant.

Conclusions

Rosiglitazone, and not fenofibrate, improves insulin sensitivity and inhibits atherosclerotic plaque formation by decreasing macrophage M1 polarization and chemotaxis in visceral adipose tissue and the vascular wall. Mechanistically, this effect involves both adiponectin, increased by rosiglitazone, and Irak3, increased by adiponectin. These results emphasize adiponectin and macrophage-associated Irak3 as indispensable molecules playing a crucial role in the anti-atherosclerotic properties of PPAR agonists.

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