Abstract 3373: MRP-8/14 is Critical for the Biological Response to Vascular Injury
Background: MRP-8 (S100A8) and MRP-14 (S100A9) are members of the S100-family of calcium-modulated proteins that regulate myeloid cell function and control inflammation, in part, through activation of toll-like receptor-4 and RAGE. Using a transcriptional profiling approach in patients with acute coronary syndromes, we made the novel discovery that MRP-14 is associated with atherothrombosis, and demonstrated that elevated plasma levels of MRP-8/14 heterodimer predict increased risk of first and recurrent cardiovascular events. Despite functioning as a pro-inflammatory mediator, the role of MRP-8/14 in vascular inflammation and disease are unknown.
Methods and Results: We evaluated vascular inflammation in wild-type (WT) and MRP-14-deficient (MRP-14−/−) mice that lack MRP-8/14 complexes with experimental arterial injury, vasculitis, or atherosclerosis. After femoral artery wire injury, MRP-14−/− mice had a 33% reduction in leukocyte accumulation (P=.0004) and a 72% reduction in cellular proliferation (P=0.001) in the arterial wall followed by a 45% reduction in neointima formation (P=0.004) compared to WT mice. In a cytokine-induced local Schwartzman-like reaction that produces thrombohemorrhagic vasculitis, MRP-14−/− mice had a 59% reduction in lesion severity (P<0.0001), an 82% smaller hemorrhagic area (P=0.015), and a 45% decline in neutrophil accumulation (P=0.013). Finally, in response to high-fat feeding, mice doubly deficient in ApoE and MRP-8/14 complexes had attenuation in atherosclerotic lesion area by 34% (P=0.023) and a 60% decrease in macrophage accumulation in plaques (P=0.021) compared to mice deficient in ApoE alone.
Conclusions: This study demonstrates that MRP-8/14 broadly regulates vascular inflammation and contributes to the biological response to vascular injury. Targeting MRP-8/14 may provide a novel therapeutic approach to modulate diverse forms of vascular injury, including restenosis, vasculitis, and atherosclerosis.