SPAG5 deficiency activates autophagy to reduce atherosclerotic plaque formation in ApoE ^-/- mice.

Publisher: BioMed Central Country of Publication: England NLM ID: 100968539 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-2261 (Electronic) Linking ISSN: 14712261 NLM ISO Abbreviation: BMC Cardiovasc Disord Subsets: MEDLINE

Original Publication: London : BioMed Central, [2001-

Apoptosis*/drug effects ; Atherosclerosis*/genetics ; Atherosclerosis*/pathology ; Autophagy*/drug effects ; Autophagy*/genetics ; Plaque, Atherosclerotic*/genetics; Animals ; Humans ; Male ; Mice ; Aorta/pathology ; Aorta/metabolism ; Aortic Diseases/pathology ; Aortic Diseases/genetics ; Aortic Diseases/prevention & control ; Aortic Diseases/metabolism ; Apolipoproteins E/genetics ; Autophagy-Related Proteins/metabolism ; Autophagy-Related Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Cycle Proteins/genetics ; Cell Proliferation/drug effects ; Cells, Cultured ; Disease Models, Animal ; Human Umbilical Vein Endothelial Cells/metabolism ; Human Umbilical Vein Endothelial Cells/pathology ; Lipoproteins, LDL/metabolism ; Mice, Inbred C57BL ; Mice, Knockout, ApoE ; Phosphatidylinositol 3-Kinase/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism

Background: Autophagy, as a regulator of cell survival, plays an important role in atherosclerosis (AS). Sperm associated antigen 5 (SPAG5) is closely associated with the classical autophagy pathway, PI3K/Akt/mTOR signaling pathway. This work attempted to investigate whether SPAG5 can affect AS development by regulating autophagy.
Methods: Human umbilical vein endothelial cells (HUVECs) were treated with oxidized-low density lipoprotein (ox-LDL) to induce cell damage. ApoE ^-/- mice were fed a Western diet to establish an AS mouse model. Haematoxylin and eosin (H&E) staining and Oil Red O staining evaluated the pathological changes and in lipid deposition in aortic tissues. CCK-8 and flow cytometry detected cell proliferation and apoptosis. Immunohistochemistry, Enzyme linked immunosorbent assay, qRT-PCR and western blotting assessed the levels of mRNA and proteins.
Results: Ox-LDL treatment elevated SPAG5 expression and the expression of autophagy-related proteins, LC3-I, LC3-II, Beclin-1, and p62, in HUVECs. GFP-LC3 dots were increased in ox-LDL-treated HUVECs and LPS-treated HUVECs. SPAG5 knockdown reversed both ox-LDL and LPS treatment-mediated inhibition of cell proliferation and promotion of apoptosis in HUVECs. SPAG5 silencing further elevated autophagy and repressed the expression of PI3K, p-Akt/Akt, and p-mTOR/mTOR in ox-LDL-treated HUVECs. 3-MA (autophagy inhibitor) treatment reversed SPAG5 silencing-mediated increase of cell proliferation and decrease of apoptosis in ox-LDL-treated HUVECs. In vivo, SPAG5 knockdown reduced atherosclerotic plaques in AS mice through activating autophagy and inhibiting PI3K/Akt/mTOR signaling pathway.
Conclusion: This work demonstrated that SPAG5 knockdown alleviated AS development through activating autophagy. Thus, SPAG5 may be a potential target for AS therapy.
(© 2024. The Author(s).)

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20202BAB206039 Natural Science Foundation of Jiangxi Province; 202130442 the Science and Technology Plan Project of Jiangxi Health Commission

Keywords: Atherosclerosis; Autophagy; PI3K/Akt/mTOR; SPAG5

0 (Apoe protein, mouse)
0 (Apolipoproteins E)
0 (Autophagy-Related Proteins)
0 (Cell Cycle Proteins)
0 (Lipoproteins, LDL)
EC 2.7.1.1 (mTOR protein, mouse)
0 (oxidized low density lipoprotein)
EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)

Date Created: 20240528 Date Completed: 20240529 Latest Revision: 20240822

20240823

PMC11131316

10.1186/s12872-024-03945-5

38807081