2. Academic Validation
  3. Thrombospondin-1 binds to integrin β3 to inhibit vascular calcification through suppression of NF-κB pathway

Thrombospondin-1 binds to integrin β3 to inhibit vascular calcification through suppression of NF-κB pathway

  • J Pathol. 2025 Mar 14. doi: 10.1002/path.6417.
Fang Liu # 1,  Qingchun Liang # 2,  Li Li # 3,  Yuan Gong 1,  Mingxi Li 4,  Liyun Feng 1,  An Chen 1,  Yuanzhi Ye 1,  Zirong Lan 1,  Yining Li 1,  Jing-Song Ou 5,  Lihe Lu 4,  Jianyun Yan 1
Affiliations

Affiliations

  • 1 Department of Cardiology, Laboratory of Heart Center, Heart Center, Zhujiang Hospital, Southern Medical University, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation; Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, PR China.
  • 2 Department of Anesthesiology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, PR China.
  • 3 Department of Cardiology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, PR China.
  • 4 Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, PR China.
  • 5 Division of Cardiac Surgery, National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, NHC Key Laboratory of Assisted Circulation, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China.
  • # Contributed equally.
PMID: 40084742 DOI: 10.1002/path.6417
Abstract

Vascular calcification is an important risk factor related to all-cause mortality of cardiovascular events in patients with chronic kidney disease (CKD). Vascular extracellular matrix (ECM) proteins have been demonstrated to regulate vascular calcification. ECM protein thrombospondin 1 (THBS1/TSP-1) plays a critical role in the regulation of vascular diseases. However, whether THBS1 is involved in vascular calcification in CKD patients remains unclear. In this study, RNA Sequencing datasets from the Gene Expression Omnibus (GEO) database GSE146638 showed that THBS1 was upregulated in the aortas of CKD rats. Enzyme-linked immunosorbent assay (elisa) revealed that serum THBS1 levels were increased in CKD patients with thoracic calcification. Western blotting and immunofluorescence analysis showed that THBS1 expression was increased in calcified vascular smooth muscle cells (VSMCs) and arteries. THBS1 knockdown exacerbated rat VSMC calcification induced by high phosphorus and calcium, as shown by Alizarin red staining and calcium content assays. Conversely, THBS1 overexpression attenuated VSMC calcification and abdominal aortic calcification in rats with CKD. Moreover, addition of recombinant THBS1 protein inhibited calcification of VSMCS and human arterial rings. Smooth muscle cell-specific knockout of THBS1 mice treated with vitamin D3 displayed aggravated aortic calcification. Mechanistically, the protein-protein interaction database STRING (http://string-db.org/) analysis and coimmunoprecipitation assays revealed THBS1 bound to Integrin β3. Reduction of Integrin β3 levels abrogated the protective effect of THBS1 on vascular calcification. RNA-seq analysis revealed that THBS1 overexpression modulated the nuclear factor-kappa B (NF-κB) signaling pathway. Of note, the inhibitory effect of THBS1 overexpression on the NF-κB signal was abolished by knockdown of Integrin β3. In conclusion, THBS1 interacts with Integrin β3 to inhibit vascular calcification through suppression of NF-κB signal, suggesting a promising therapeutic target for vascular calcification in CKD. © 2025 The Pathological Society of Great Britain and Ireland.

Keywords

NF‐κB; chronic kidney disease; extracellular matrix; integrin β3; thrombospondin 1; vascular calcification.

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