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Introduction
Atherosclerosis (AS) is a complex process involving numerous cell types and important cell-to-cell interactions that ultimately lead to progression from the 'fatty streak' to formation of more complex atherosclerotic plaques (1–4). The initiation of AS is multifactorial and caused by a collection of risk factors (3–5). The precise initiating event is unknown; however, dysfunction within the endothelium is thought to be an important early contributor and results in the earliest detectable changes in the life history of an atherosclerotic lesion (1,5–9). The endothelium is crucial for maintenance of vascular homeostasis, ensuring that a balance remains between vasoactive factors controlling its permeability, adhesiveness, and integrity (1,5,7). Endothelial cell (EC) activation or injury by a variety of stimuli including pro-inflammatory cytokines, certain bacterial endotoxins and hemodynamic factors, leads to local thrombosis, loss of vessel barrier function, and rapid and robust leukocyte recruitment (5,10,11). If unchecked, these alterations can contribute to cardiovascular diseases including AS, ischemia/reperfusion injury, rheumatoid arthritis and allograft rejection (5,6). One of the important links between AS and pro-inflammatory endothelial activation is the intrinsic capacity of activated vascular endothelium to synthesize and secrete chemokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), thus generating localized, intercellular autocrine and paracrine signaling loops within the vessel wall (1,12,13). Indeed, cytokines are produced by and act on almost all cells involved in the pathogenesis of AS, participating in all steps of the process, from the early endothelial dysfunction to the late formation and disruption of a vulnerable plaque (14,15). Thus detecting early injury or pro-inflammatory endothelial activation will shed light on mechanisms that are responsible for inflammation/injury-initiated AS.
In recent years, it has been shown that many cellular regulatory processes depend on the post-translational functions of ubiquitin and ubiquitin-like proteins (Ubls), including transcription, DNA repair, signal transduction, autophagy, cell proliferation, differentiation, apoptosis, endoplasmic reticulum (ER) regulation, inflammation, antigen processing and stress responses (16–18). Ubiquitin-fold modifier 1 (Ufm1) has recently been identified as a novel Ubl with a molecular mass of 9.1 kDa, and it appears to have a similar tertiary structure to ubiquitin, despite having little (16%) amino acid sequence identity (19). Similar to the process of protein ubiquitination, Ufm1 is first synthesized in a pro-form and is cleaved at the C-terminus by the specific cysteine proteases,...