2. Academic Validation
  3. Ganglioside GM3 Protects Against Abdominal Aortic Aneurysm by Suppressing Ferroptosis

Ganglioside GM3 Protects Against Abdominal Aortic Aneurysm by Suppressing Ferroptosis

  • Circulation. 2024 Mar 12;149(11):843-859. doi: 10.1161/CIRCULATIONAHA.123.066110.
Fangni Zhang # 1 2,  Kan Li # 2,  Wenhui Zhang 2,  Ziyan Zhao 2,  Fangyuan Chang 2,  Jie Du 2 3 4 5 6,  Xu Zhang 2,  Kaiwen Bao 7,  Chunyong Zhang 7,  Lei Shi 7,  Zongwei Liu 8,  Xiangchen Dai 8,  Chen Chen 9,  Dao Wen Wang 9,  Zhong Xian 10,  Hongfeng Jiang 10,  Ding Ai 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Tianjin Institute of Cardiology, The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Second Hospital of Tianjin Medical University, Tianjin Medical University, China (F.Z., D.A.).
  • 2 Department of Physiology and Pathophysiology (F.Z., K.L., W.Z., Z.Z., F.C., J.D., X.Z., D.A.).
  • 3 Beijing Anzhen Hospital, Capital Medical University, China (J.D.).
  • 4 The Key Laboratory of Remodeling Cardiovascular Diseases, Ministry of Education, China (J.D.).
  • 5 Collaborative Innovation Center for Cardiovascular Disorders, Beijing, China (J.D.).
  • 6 Beijing Institute of Heart, Lung and Blood Vessel Diseases, China (J.D.).
  • 7 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences (K.B., C.Z., L.S.), Tianjin Medical University, China.
  • 8 Department of Vascular Surgery, Tianjin Medical University General Hospital, China (Z.L., X.D.).
  • 9 Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China (C.C., D.W.W.).
  • 10 Experimental Research Center, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, China (Z.X., H.J.).
  • # Contributed equally.
PMID: 38018467 DOI: 10.1161/CIRCULATIONAHA.123.066110
Abstract

Background: Abdominal aortic aneurysm (AAA) is a potentially life-threatening vascular condition, but approved medical therapies to prevent AAA progression and rupture are currently lacking. Sphingolipid metabolism disorders are associated with the occurrence and development of AAA. It has been discovered that ganglioside GM3, a sialic acid-containing type of glycosphingolipid, plays a protective role in atherosclerosis, which is an important risk factor for AAA; however, the potential contribution of GM3 to AAA development has not been investigated.

Methods: We performed a metabolomics study to evaluated GM3 level in plasma of human patients with AAA. We profiled GM3 synthase (ST3GAL5) expression in the mouse model of aneurysm and human AAA tissues through Western blotting and immunofluorescence staining. RNA Sequencing, affinity purification and mass spectrometry, proteomic analysis, surface plasmon resonance analysis, and functional studies were used to dissect the molecular mechanism of GM3-regulating Ferroptosis. We conditionally deleted and overexpressed St3gal5 in smooth muscle cells (SMCs) in vivo to investigate its role in AAA.

Results: We found significantly reduced plasma levels of GM3 in human patients with AAA. GM3 content and ST3GAL5 expression were decreased in abdominal aortic vascular SMCs in patients with AAA and an AAA mouse model. RNA Sequencing analysis showed that ST3GAL5 silencing in human aortic SMCs induced Ferroptosis. We showed that GM3 interacted directly with the extracellular domain of TFR1 (Transferrin Receptor 1), a cell membrane protein critical for cellular iron uptake, and disrupted its interaction with holo-transferrin. SMC-specific St3gal5 knockout exacerbated iron accumulation at lesion sites and significantly promoted AAA development in mice, whereas GM3 supplementation suppressed lipid peroxidation, reduced iron deposition in aortic vascular SMCs, and markedly decreased AAA incidence.

Conclusions: Together, these results suggest that GM3 dysregulation promotes Ferroptosis of vascular SMCs in AAA. Furthermore, GM3 may constitute a new therapeutic target for AAA.

Keywords

aortic aneurysm, abdominal; ferroptosis; gangliosides; myocytes, smooth muscle; sphingolipids.

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