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  3. Apolipoprotein C3 exacerbates vascular calcification by promoting ferroptosis via the TLR2/AMPK pathway in vascular smooth muscle cells

Apolipoprotein C3 exacerbates vascular calcification by promoting ferroptosis via the TLR2/AMPK pathway in vascular smooth muscle cells

  • Redox Biol. 2026 Apr:91:104088. doi: 10.1016/j.redox.2026.104088.
Zihao Zhou 1,  Jinxuan Chen 2,  Huan Wang 2,  Yufei Han 2,  Changyun Liu 2,  Qiang Shen 2,  Zhao Dong 2,  Kaikai Lu 2,  Chao Zhai 3,  Yitong Xu 2,  Lianxin Zhang 2,  Lei He 4,  Yuan Fang 2,  Ling Zhang 2,  Yuhui Wang 2,  Xunde Xian 2,  Lin Yao 5,  Erdan Dong 6,  Wei Huang 7
Affiliations

Affiliations

  • 1 Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China; Department of Laboratory Medicine, Peking University Third Hospital, Beijing, 100191, China.
  • 2 Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China.
  • 3 Department of Cardiology, Peking University First Hospital, Beijing, 100035, China.
  • 4 Department of Urology, Peking University First Hospital, Beijing, 100035, China.
  • 5 Department of Urology, Peking University First Hospital, Beijing, 100035, China. Electronic address: [email protected].
  • 6 Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China; Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, 100191, China; Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, 266113, China; Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, China. Electronic address: [email protected].
  • 7 Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China. Electronic address: [email protected].
PMID: 41734579 DOI: 10.1016/j.redox.2026.104088
Abstract

Background: Vascular calcification (VC) is prevalent in patients with chronic renal failure (CRF), and it is closely related to the morbidity and mortality of cardiovascular diseases; however, no medical treatments are available for this condition. Recent clinical studies have shown that plasma Apolipoprotein C3 (apoC3) levels are positively correlated with VC. However, whether apoC3 is involved in VC remains unclear.

Methods: Sections of calcified renal arteries from CRF patients were immunostained to measure calcium deposition and apoC3 expression. VC was induced in apoC3 transgenic (Tg) and knockout (KO) mice by both 5/6 nephrectomy and vitamin D3-overload. The arterial rings from mice or humans and primary rat vascular smooth muscle cells (VSMCs) were incubated with high-phosphate to study the effect of apoC3 on VC ex vivo and in vitro respectively. The calcification and Ferroptosis related parameters were studied. The mechanisms involved were also investigated.

Results: apoC3 expression levels were increased in calcified arteries from mice and patients with CRF. apoC3 overexpression exacerbated calcium deposition in the calcified aortas from Tg mice in vivo, and in calcified aortic rings of Tg mice ex vivo and VSMCs infected by adenovirus of apoC3 in vitro. Consistently with these findings, apoC3 deficiency alleviated these effects. Furthermore, apoC3 overexpression increased Ferroptosis in calcified aortas and VSMCs, whereas apoC3 deficiency suppressed Ferroptosis. Further investigation revealed that apoC3 inhibited the AMPK/NRF2 signaling pathway through Toll-like Receptor 2 (TLR2) in calcified VSMCs, downregulated the expression of solute carrier family 7 member 11 (SLC7A11) and Glutathione Peroxidase 4 (GPX4), subsequently increased lipid peroxidation and promoted Ferroptosis, ultimately exacerbating calcification in the VSMCs. Furthermore, we found that knockdown of apoC3 by siRNA remarkably attenuated calcification of renal arterial rings in humans.

Conclusions: We demonstrated that apoC3 exacerbated VC and increased the osteogenic transdifferentiation in VSMCs by increasing Ferroptosis. apoC3 might be a potential target for VC treatment.

Keywords

Apolipoprotein C3; Chronic kidney disease; Ferroptosis; Vascular calcification; Vascular smooth muscle cells.

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