Role of Extracellular RNA in Atherosclerotic Plaque Formation in Mice

Abstract

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)-1β, 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 × 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.

Bovine Brain Ribonuclease Is the Functional Homolog of Human Ribonuclease 1

“…Further studies, including analyses of mammalian animal models, are necessary for a complete description of the most significant biological functions of RNase 1 in humans and other mammals. Currently, mouse studies probing the therapeutic potential of RNase 1 against various pathologies have utilized RNase A as their treatment of choice (7,8,10,11,15,77). We speculate that the use of recombinant human RNase 1, BRB, or mouse RNase 1 would provide a more robust and relevant phenotype.…”

Noninvasive Molecular Ultrasound Monitoring of Vessel Healing After Intravascular Surgical Procedures in a Preclinical Setup

“…VCAM-1 is expressed by activated VSMCs and it is accessible for intravascular targeting after arterial denudation, whereas replicating ECs express VCAM-1 during endothelial reconstruction until regeneration 10,11 (Figure I in the online-only Data Supplement). We, therefore, used VCAM-1-targeted MBs (MB VCAM-1 ) and molecular ultrasound to monitor arterial endothelial recovery, and validated the results using twophoton laser scanning microscopy (TPLSM) as a deep-tissue imaging modality.…”

Influence of Extracellular RNAs, Released by Rheumatoid Arthritis Synovial Fibroblasts, on Their Adhesive and Invasive Properties

“…exRNA mediates tumor progression and atherogenesis by inducing TNF-a release and promoting macrophage polarization (19,20). A role of exRNA in coagulation, vascular permeability, edema, and thrombus formation was also described (9,21).…”