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

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.

Knockdown of hsa_circ_0000729 Inhibits the Tumorigenesis of Non-Small Cell Lung Cancer Through Mediation of miR-1281/FOXO3 Axis

“…Furthermore, miR-1281 antagomir partially reversed hsa_circ_0000729 knockdown-induced cell growth inhibition of NSCLC (Figure 4G-I). Since cleaved caspase 1, GSDME-N and IL-18 were known to be key mediators in pyroptosis, 16,17 it could be suggested that hsa_circ_0000729 knockdown-induced pyroptosis in NSCLC cells was through sponging miR-1281.…”

Differential expression analyses on aortic tissue reveal novel genes and pathways associated with abdominal aortic aneurysm onset and progression

“…SPP1 codes for the osteopontin protein, an important regulator of inflammation that has described functions in cardiovascular diseases[45]. SPP1 is more expressed in AAA tissue than controls, both in animal models and in humans, and it participates in AAA-associated extracellular matrix degradation[46,47] through the nuclear factor kappa B signaling pathway. It is also known that the SPP1 gene undergoes splicing and gives rise to 3 distinct isoforms osteopontin a, osteopontin b and osteopontin c, with specific characteristics, which have not been characterized in AAA.…”

“…Regarding the SPP1 gene, we found six genetic variants (rs35893069 (MAF (T) = 0.1), rs6839524 (MAF (G) = 0.12), rs4754 (MAF (C) = 0.28), rs1126616 (MAF (T) = 0.27), rs1126772 (MAF (G) = 0.21), rs9138 (MAF (C) = 0.22)) with allele specific expression among the twelve AAA samples. As previously discussed, the SPP1 has been associated to AAA risk due to the role of the protein osteopontin, which it encodes, in the degradation of the extracellular matrix that is characteristic of AAA[46,47]. However, none of the six genetic variants were found to be significant in the previous GWAS[7], and therefore no association with allelic expression could be established.…”

“…As previously discussed, the SPP1 has been associated to AAA risk due to the role of the protein osteopontin, which it encodes, in the degradation of the extracellular matrix that is characteristic of AAA [46,47]. However, none of the six genetic variants were found to be significant in the previous GWAS [7], and therefore no association with allelic expression could be established.…”

β‐catenin‐controlled tubular cell‐derived exosomes play a key role in fibroblast activation via the OPN‐CD44 axis

“…In the diseased state, full‐length OPN is often cleaved into an N‐terminal fragment (∼50 kDa) and two C‐terminal fragments (∼18 and ∼16 kDa) (Hoac et al., 2018 ). N‐OPN could be the major active form to trigger a series of pathological changes (Hattori et al., 2021 ; Liu et al., 2021 ). However, the role of N‐OPN in kidney injury has not been investigated yet.…”