Fibronectin Overexpression Modulates Formation of Macrophage Foam Cells by Activating SREBP2 Involved in Endoplasmic Reticulum Stress

• Main Authors: Hansong Du, Yu Wang, Zhengfeng Zhang, Jing Yang, Jie Zhang, Ying Zhang
• Format: Article
• Language: English
• Published: Cell Physiol Biochem Press GmbH & Co KG 2015-07-01
• Series: Cellular Physiology and Biochemistry
• Subjects: Fibronectin; ER stress; SREBP2; Foam cells
• Online Access: http://www.karger.com/Article/FullText/430153
• ISSN: 1015-8987; 1421-9778

Aims: To explore the explicit role of fibronectin (FN) isforms in atherosclerotic lesions and the underlying mechanisms. Methods and Results: Inducible stable expression was performed, and similar results were observed between EDA+FN (FN containing EDA domain) and EDA-FN (FN devoid of EDA domain). FN isforms could trigger endoplasmic reticulum (ER) stress, thereby leading to lipid accumulation in cultured Raw264.7 cells. FN isforms-induced gene expression and lipid accumulation were inhibited by a chemical chaperone 4-phenyl butyric acid (PBA) or by overexpression of the ER chaperone, GRP78/BiP, demonstrating a direct role of ER stress in activation of cholesterol/triglyceride biosynthesis. Moreover, activation of the sterol regulatory element binding protein-2 (SREBP2) was found to be downstream of ER stress, and this activation was affirmed to account for the intracellular accumulation of cholesterol using RNAi technique. Conclusion: our study suggests that enhanced FN in lesions facilitates foam cell formation due to dysregulation of the endogenous sterol response pathway by activation of ER stress, and confirms that EDA+FN has no more pro-atherogenic role than EDA-FN in triggering ER stress.