Oxidized low-density lipoprotein induced hepatoma-derived growth factor upregulation mediates foam cell formation of cultured rat aortic vascular smooth muscle cells

• Published in: European journal of cell biology 2021-06, Vol.100 (5-6), p.151169-151169, Article 151169
• Main Authors: Cheng, Cheng-I, Tai, Ming-Hong, Chang, Huoy-Rou, Chou, Ming-Huei, Chen, Guan-Ting, Chen, Po-Han, Kao, Ying-Hsien
• Format: Article
• Language: English
• Subjects: Animals; Atherogenesis; CD36; Cells, Cultured; Foam cell formation; Foam Cells - metabolism; Intercellular Signaling Peptides and Proteins; Lipoproteins, LDL - metabolism; LOX-1; Muscle, Smooth, Vascular; Oxidized LDL; Phosphatidylinositol 3-Kinases; Rats; Signal transduction; Up-Regulation
• ISSN: 0171-9335; 1618-1298
• DOI: 10.1016/j.ejcb.2021.151169

[Display omitted] •OxLDL exposure upregulates expression and release of HDGF in cultured aortic SMCs.•HDGF modulates atherogenic regulator expression and enhances oxLDL-induced foam cell formation in SMCs.•PI3K/Akt and MAPK activation is involved in oxLDL-induced HDGF, LOX-1, and CD36 upregulation.•HDGF gene silencing ameliorates oxLDL-induced atherogenic regulator upregulation and foam cell formation.•The oxLDL/LOX-1/HDGF axis may serve as a target for anti-atherogenesis. Vascular smooth muscle cells (SMCs) are important vascular components that are essential for the regulation of vascular functions during vascular atherosclerogenesis and vascular injury. Oxidized low-density lipoprotein (oxLDL) is known to induce SMC activation and foam cell transformation. This study characterized the role of hepatoma-derived growth factor (HDGF) in oxLDL-induced foam cell formation in cultured primary rat aortic SMCs. OxLDL exposure significantly increased HDGF expression and extracellular release. It also upregulated atherogenic regulators in SMCs, including TLR4, MyD88, LOX-1, and CD36. Exogenous HDGF stimulation not only increased the expression of cognate receptor nucleolin, but also the innate immunity regulators TLR4/MyD88 and lipid metabolism regulators, including LOX-1 and CD36. Oil red O staining showed that HDGF did not initiate, but enhanced oxLDL-driven foam cell formation in SMCs. Further signaling characterization demonstrated that oxLDL evoked activation of PI3K/Akt and p38 MAPK signaling pathways, both of which were involved in the upregulation of HDGF, LOX-1, and CD36 induced by oxLDL. Gene knockdown experiments using LOX-1 targeted siRNA demonstrated that LOX-1 expression was critical for oxLDL-induced HDGF upregulation, while HDGF gene depletion completely abolished oxLDL-triggered TLR4, LOX-1, and CD36 overexpression and foam cell formation in SMCs. These findings strongly suggest that oxLDL-induced HDGF upregulation participates in subsequent LOX-1 and CD36 expression in aortic SMCs and mechanistically contributes to the formation of SMC-derived foam cells. The oxLDL/LOX-1/HDGF axis may serve as a target for anti-atherogenesis therapy.