The Role of Extracellular RNA in Atherosclerotic Plaque Formation in Mice
Background—Atherosclerosis and vascular remodeling after injury are driven by inflammation and mononuclear cell infiltration. Extracellular RNA (eRNA) has recently been implicated to become enriched at sites of tissue damage, and to act as a pro-inflammatory mediator. We here addressed the role of eRNA in high-fat-diet (HFD)-induced atherosclerosis and neointima formation after injury in atherosclerosis-prone mice.
Methods and Results—The presence of eRNA was revealed in atherosclerotic lesions from HFD-fed low density lipoprotein receptor-deficient (Ldlr-/-) mice in a time-progressive fashion. RNase activity in plasma increased within the first 2 weeks (44 ± 9 vs. 70 ± 7 mU/mg protein; p=0.0012), followed by a decrease to levels below baseline after 4 weeks of HFD (44 ± 9 vs. 12 ± 2 mU/mg protein; p<0.0001). Exposure of bone marrow-derived macrophages to eRNA resulted in a concentration-dependent upregulation of the pro-inflammatory mediators tumor necrosis factor-α, arginase-2, Interleukin (IL)-1ß, IL-6 and Interferon-γ. In a model of accelerated atherosclerosis after arterial injury in apolipoprotein E-deficient (apoE-/-) mice, treatment with RNase1 diminished the increased plasma level of eRNA, evidenced after injury. Likewise, RNase1 administration reduced neointima formation compared to vehicle-treated apoE-/- controls (25.0 ± 6.2 vs. 46.9 ± 6.9 x 103 μm2, p=0.0339), and was associated with a significant decrease in plaque macrophage content. Functionally, RNase1 treatment impaired monocyte arrest on activated smooth muscle cells under flow conditions in vitro, and inhibited leukocyte recruitment to injured carotid arteries in vivo.
Conclusions—As eRNA is associated with atherosclerotic lesions and contributes to inflammation-dependent plaque progression in atherosclerosis-prone mice, its targeting with RNase1 may serve as a new treatment option against atherosclerosis.
- Received March 12, 2013.
- Revision received October 27, 2013.
- Accepted October 28, 2013.