Angiotensin Ⅱ activates p53/SAT1 signaling pathway to induce ferroptosis in white adipocytes
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Institute of Cardiovascular Disease, University of South China & Key Lab for Arteriosclerology of Hunan Province & Hunan Province Arteriosclerotic Disease International Scientific and Technological Innovation Cooperation Base, Hengyang, Hunan 421001, China)

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R363;R5

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    Abstract:

    Aim To investigate the effect and mechanism of angiotensin Ⅱ (AngⅡ) on ferroptosis in white adipocytes. Methods The 3T3-L1 preadipocytes were differentiated into white adipocytes by inducer stimulation. The experiment was divided into control group, AngⅡ group, AngⅡ+ Fer-1(ferroptosis inhibitor) group and AngⅡ+ PFT-α (p53 inhibitor) group. AngⅡwas used to treat cells. RT-qPCR and Western blot were used to detect the expression levels of ferroptosis factors and adipokines. JC-1 kit was used to detect mitochondrial membrane potential (MMP) level.Iron ion kit was used to detect intracellular iron content. Glutathione (GSH) kit was used to detect GSH content. Fer-1 and AngⅡ were added to treat cells to detect the the changes of ferroptosis level. The expression of p53 and spermidine/spermine N1-acetyltransferase 1 (SAT1) protein was detected. Subsequently, PFT-α and AngⅡ were added to co-treat cells to detect the changes of p53 and SAT1 protein expression, and to observe the effect of inhibiting p53 expression on the expression levels of ferroptosis factors and adipokines. Results 3T3-L1 cells were successfully differentiated into white adipocytes by stimulator-induced differentiation. AngⅡ induced ferroptosis in white adipocytes. RT-qPCR results showed that compared with control group, the mRNA expression of anti-ferroptosis factor glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11) and iron regulatory protein 1 (IRP-1) was down-regulated in AngⅡ group, and the mRNA expression of pro-ferroptosis factor acyl-CoA synthetase of long-chain family member 4 (ACSL4) was up-regulated. Western blot results showed that compared with control group, the protein expression of SLC7A11 and GPX4 was down-regulated in AngⅡ group, and the protein expression of ACSL4 was up-regulated. AngⅡ treatment increased the content of intracellular iron ions and decreased the levels of GSH and MMP. Compared with AngⅡ group, the mRNA expression of IRP-1 and SLC7A11 was up-regulated in AngⅡ+Fer-1 group. AngⅡ induced changes in the expression profile of adipokines in white adipocytes. Western blot results showed that compared with control group, the protein expression of pro-inflammatory adipokine leptin (LEP), resistin (RETN), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was up-regulated in AngⅡ group, and the protein expression of anti-inflammatory adipokine adiponectin (ADPN) and omentin 1 (ITLN1) was down-regulated. In addition, AngⅡ increased the protein expression of p53 and SAT1. Inhibition of p53 expression can improve the level of ferroptosis and adipokine expression in white adipocytes treated with AngⅡ. Western blot results showed that compared with AngⅡ group, the protein expression of p53 and SAT1 was down-regulated in AngⅡ + PFT-α group, the protein expression of SLC7A11 and GPX4 was up-regulated, and the protein expression of ACSL4 was down-regulated. The protein expression of ADPN was up-regulated in AngⅡ+ PFT-α group, and the protein expression of TNF-α, LEP and RETN was down-regulated. Conclusion AngⅡ induces ferroptosis in white adipocytes through activating the p53/SAT1 signaling pathway.

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DENG Wei, LIU Xiyan, GUO Liyuan, XU Qian, ZHOU Kun, ZHAO Yuanqin, WANG Zhaoyue, LI Xiang, DENG Xinmei, QIN Xinyi, REN Zhong, JIANG Zhisheng. Angiotensin Ⅱ activates p53/SAT1 signaling pathway to induce ferroptosis in white adipocytes[J]. Editorial Office of Chinese Journal of Arteriosclerosis,2025,33(5):385-394.

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History
  • Received:November 27,2024
  • Revised:February 17,2025
  • Online: June 03,2025
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