Abstract
Ribosome biogenesis is a crucial biological process related to cell proliferation, redox balance, and muscle contractility. Aortic smooth muscle cells (ASMCs) show inhibition of proliferation and apoptosis, along with high levels of oxidative stress in aortic dissection (AD). Theoretically, ribosome biogenesis should be enhanced in the ASMCs at its proliferative state but suppressed during apoptosis and oxidative stress. However, the exact status and role of ribosome biogenesis in AD are unknown. We therefore analyzed the expression levels of BOP1, a component of the PeBoW complex which is crucial to ribosome biogenesis, in AD patients and a murine AD model and its influence on the ASMCs. BOP1 was downregulated in the aortic tissues of AD patients compared to healthy donors. In addition, overexpression of BOP1 in human aortic smooth muscle cells (HASMCs) inhibited apoptosis and accumulation of p53 under hypoxic conditions, while knockdown of BOP1 decreased the protein synthesis rate and motility of HASMCs. The RNA polymerase I inhibitor cx-5461 induced apoptosis, ROS production, and proliferative inhibition in the HASMCs, which was partly attenuated by p53 knockout. Furthermore, cx-5461 aggravated the severity of AD in vivo, but a p53-/- background extended the life-span and lowered AD incidence in the mice. Taken together, decreased ribosome biogenesis in ASMCs resulting in p53-dependent proliferative inhibition, oxidative stress, and apoptosis is one of the underlying mechanisms of AD.
Highlights
According to the Global Burden Disease 2010 report, the death rate from aortic aneurysms (AA) and aortic dissection (AD) increased from 2.49 per 100,000 to 2.78 per 100,000 between 1990 and 2010, with higher frequencies among men [1, 2]
BOP1 is the crucial component of PeBoW complex, which regulates ribosomal RNA (rRNA) processing, and due to its short halflife on account of the PEST motif, it might be indicative of rRNA maturation
Since ribosome biogenesis is closely related to p53, we further examined the in situ p53 expression and found significant elevation and nuclear accumulation (Figure 1(c)) in the aorta of AD patients (n = 28) compared to donors (n = 14) (Figures 1(c) and 1(d))
Summary
According to the Global Burden Disease 2010 report, the death rate from aortic aneurysms (AA) and aortic dissection (AD) increased from 2.49 per 100,000 to 2.78 per 100,000 between 1990 and 2010, with higher frequencies among men [1, 2]. The common pathological basis of both is aortic media degeneration (AMD), which is characterized by a decrease in the number of aortic smooth muscle cells (ASMCs) [3] and matrix degeneration [4]. The phenotypic transformation of the ASMCs from the contractile to the proliferative form is involved in the process of AMD. Studies show that atrophy of the skeletal muscle is partly due to impaired ribosome genesis [6, 7], while hypertrophy is associated with enhanced ribosome biogenesis [8, 9]. In the context of AMD, one can surmise that ribosome biogenesis is enhanced to aid ASMC proliferation. Since decreased contractility is another significant change that occurs in the ASMCs during AMD, ribosome biogenesis ought to decrease in these cells. The ribosomal status in ASMCs during AMD needs to be clarified
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