Work

A20 and TNIP-3 Reduce NF-κB-Mediated Paracrine Responses to Hypoxia/Hyperglycemia-Induced Endothelial Senescence

Year: 2025

Type: article

Abstract: BACKGROUND: Hypoxia and ageing both involve impaired oxygen delivery, leading to oxidative damage, and endothelial cell (EC) dysfunction. In the presence of chronic hyperglycemia, these effects are amplified, accelerating EC senescence and vascular impairment. METHODS: ) followed by 2 h of reoxygenation. RESULTS: ECs exposed to high glucose and hypoxia developed a senescent phenotype, as indicated by increased expression of p21 and p16, and elevated β-galactosidase staining. Interestingly, hypoxia-induced senescence did not coincide with the classical senescence-associated secretory phenotype (SASP). Compared to normoxia, ECs exposed to hypoxia, particularly under high-glucose conditions, showed reduced NF-κB-driven proinflammatory secretome (MCP-1, IL-6, IL-8), downregulation of the NF-κB p50 subunit, and simultaneous upregulation of the angiogenic factor VEGF-A with downregulation of YAP-1, a key regulator of cell survival. Notably, we observed a strong upregulation of A20 and TNIP-3, two well-characterized negative regulators of NF-κB signalling. CONCLUSIONS: Hypoxia-induced senescence did not trigger a typical inflammatory SASP. Although ECs enter a senescent state, they activate an anti-inflammatory response, suppressing NF-κB signalling and increasing the expression of its inhibitors, A20 and TNIP-3. This may reflect a non-canonical senescence response whose functional significance remains to be determined.

Source: Cells

DOI: 10.3390/cells14231908

Authors: Lara Russo, Serena Babboni, Serena Del Turco, Giuseppina Basta

Institutions: Istituto di Fisiologia Clinica, National Research Council

Language: English

Topic: Telomeres, Telomerase, and Senescence

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,258