Osteopontin N-Terminal Function in an Abdominal Aortic Aneurysm From Apolipoprotein E-Deficient Mice.

Hongyang Liu,Wei Song,Yancui Sun,Ying Zhang,Yinong Jiang

doi:10.3389/fcell.2021.681790

Abstract

The cleavage of osteopontin (OPN) by thrombin results in an N-terminal fragment (OPN-N), which exposes a cryptic integrin-binding motif that promotes the adherence of cells, and plays a proinflammatory role. However, the effect of OPN-N on abdominal aortic aneurysm (AAA) remains unknown. The aim of this study was to investigate the expression of OPN-N in aortic tissue samples obtained from patients, who underwent acute aortic dissection (AD), and normal aorta, effect of OPN-N on angiotensin (Ang) II-induced AAA in mice, and relationship between OPN-N and pyroptosis-related inflammatory factors in vitro. Hematoxylin and eosin staining was conducted to detect histological changes. Next, we detected the expression of the OPN-N protein. Additionally, ApoE−/− mice were divided into four groups: control, control + M5Ab (to block the OPN-N function in mice), Ang II, and Ang II + M5Ab. All mice were euthanized after a 28-day infusion and whole aortas, including thoracic and abdominal aortas, were collected for morphological and histological analysis of the AAA. The OPN-N protein expression was higher in patients with AD than in normal individuals, while histological changes in the aortas of Ang II mice were suppressed in Ang II + M5Ab mice. The expression of OPN-N, NOD-, LRR-, and pyrin domain-containing protein 3, pro-Caspase-1, ASC, Gasdermin-d, interleukin (IL)-18, IL-1β, matrix metalloproteinase (MMP) 2, and MMP9 was lower in the Ang II + M5Ab group than in the Ang II group. The gene expression of monocyte chemoattractant protein-1, IL-6, and tumor necrosis factor-α was suppressed in the aortic tissues of the Ang II + M5Ab group compared with the Ang II group. Moreover, the expression of α-smooth muscle actin was lower in the Ang II group than in the Ang II + M5Ab group. In vitro results showed that the increase in the expression of pyroptosis-related inflammatory factors induced by OPN was mediated through the nuclear factor (NF)-κB pathway. In conclusion, OPN-N promotes AAA by increasing the expression of pyroptosis-related inflammatory factors through the NF-κB pathway, inflammation, and extracellular matrix degradation. These results highlight the potential of OPN-N as a new therapeutic target to prevent AAA expansion.

Highlights

Abdominal aortic aneurysm (AAA) is a cardiovascular disease characterized by aortic dilation that exceeds the normal diameter by 50% (Nordon et al, 2011)
We observed that angiotensin II (Ang II) infusion, over 28 days, upregulated OPN-N levels in ApoE−/− mice when compared with the control group
M5Ab inhibited the expression of OPN-N in the Ang II + M5Ab group, in comparison with the Ang II group, indicating that administration with M5Ab attenuated the effect of OPN-N in Ang II-induced AAA

Summary

Introduction

Abdominal aortic aneurysm (AAA) is a cardiovascular disease characterized by aortic dilation that exceeds the normal diameter by 50% (Nordon et al, 2011). Previous studies have shown that inflammatory cells secrete various inflammatory factors, including cytokines, chemokines, reactive oxygen species, and immunoglobulins (Ihara et al, 1999; Vanderlaan and Reardon, 2005; Liu et al, 2019). This causes macrophages and lymphocytes to infiltrate the arterial wall, which results in the release of excess matrix metalloproteinase (MMP), degradation of elastin in the aortic wall, phenotype switch and loss of vascular smooth muscle cells (VSMCs), and compensatory collagen deposition (Raffort et al, 2017; Maguire et al, 2019; Wang S. et al, 2020). The fully active Caspase-1 cleaves pro-IL-1β and pro-IL-18 into their biologically active forms as well as Gasdermin-d (GSDMD), which is necessary for the secretion of cytosolic contents, and induce lytic cell death termed “pyrotosis” (Takahashi, 2021)

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