2. Academic Validation
  3. Inhibition of Hedgehog signaling ameliorates foam cell formation by promoting autophagy in early atherosclerosis

Inhibition of Hedgehog signaling ameliorates foam cell formation by promoting autophagy in early atherosclerosis

  • Cell Death Dis. 2023 Nov 14;14(11):740. doi: 10.1038/s41419-023-06270-5.
Yuting Zhang # 1,  Weijuan Xin # 2,  Xiaozhi Hu # 1,  Hanqi Wang # 1,  Xiaomiao Ye 3,  Caili Xu 1,  Yanyang Nan 1,  Zhengyu Wu 4,  Dianwen Ju 5 6,  Jiajun Fan 7
Affiliations

Affiliations

  • 1 Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China.
  • 2 Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China.
  • 3 Department of Cardiology, Minhang Hospital, Fudan University, 170 Xinsong Road, Shanghai, 201199, China.
  • 4 TAU Cambridge Ltd, The Bradfield Centre UNIT 184, Cambridge Science Park, CB4 0GA, Cambridge, UK. wuzhengy@hotmail.com.
  • 5 Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China. dianwenju@fudan.edu.cn.
  • 6 Fudan Zhangjiang Institute, Shanghai, 201203, China. dianwenju@fudan.edu.cn.
  • 7 Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China. jiajunfan12@fudan.edu.cn.
  • # Contributed equally.
PMID: 37963874 DOI: 10.1038/s41419-023-06270-5
Abstract

Macrophages are the origin of most foam cells in the early stage of atherosclerotic plaques. However, the mechanism involved in the formation of macrophage-derived foam cell formation remains unclear. Here, we revealed that the Hedgehog (Hh) signaling is critical in autophagy-lysosome pathway regulation and macrophage-derived foam cell formation. Inhibition of Hh signaling by vismodegib ameliorated lipid deposition and oxidative stress level in atherosclerotic plaques in high-fat diet-fed apoE-/- mice. For mechanistic study, how the Hh signaling modulate the process of foam cell formation were accessed afterward. Unexpectedly, we found that suppression of Hh signaling in apoE-/- mice had no significant impact on circulating Cholesterol levels, indicating that Hh pathway modulate the procession of atherosclerotic plaque not through a traditional lipid-lowing mechanism. Instead, vismodegib was found to accelerate autophagosomes maturation as well as Cholesterol efflux in macrophage-derived foam cell and in turn improve foam cell formation, while Autophagy inhibitors (LY294002 or CQ) administration significantly attenuated vismodegib-induced Cholesterol efflux and reversed the effect on foam cell formation. Therefore, our result demonstrated that inhibition of the Hh signaling pathway increases Cholesterol efflux and ameliorates macrophage-derived foam cell formation by promoting Autophagy in vitro. Our data thus suggested a novel therapeutic target of atherosclerosis and indicated the potential of vismodegib to treat atherosclerosis.

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