Abstract
PURPOSE: Inflammation is a hallmark of many diseases, such as atherosclerosis, autoimmune diseases, obesity, and cancer. Isoflavone-free soy protein diet (SPI(-)) has been shown to reduce atherosclerotic lesions in a hyperlipidemic mouse model compared to casein (CAS)-fed mice, despite unchanged serum lipid levels. However, possible mechanisms contributing to the athero-protective effect of soy protein remain unknown. Therefore, we investigated whether and how SPI(-) diet inhibits inflammatory responses associated with atherosclerosis. METHODS: Apolipoprotein E knockout (apoE-/-) mice (5-week) were fed CAS or SPI(-) diet for 1 or 5 week to determine LPS- and hyperlipidemia-induced acute and chronic inflammatory responses, respectively. Expression of NF-κB-dependent inflammation mediators such as VCAM-1, TNF-α, and MCP-1 were determined in aorta and liver. NF-κB, MAP kinase, and AKT activation was determined to address mechanisms contributing to the anti-inflammatory properties of soy protein/peptides. RESULTS: Isoflavone-free soy protein diet significantly reduced LPS-induced VCAM-1 mRNA and protein expression in aorta compared to CAS-fed mice. Reduced VCAM-1 expression in SPI(-)-fed mice also paralleled attenuated monocyte adhesion to vascular endothelium, a critical and primary processes during inflammation. Notably, VCAM-1 mRNA and protein expression in lesion-prone aortic arch was significantly reduced in apoE-/- mice fed SPI(-) for 5 weeks compared with CAS-fed mice. Moreover, dietary SPI(-) potently inhibited LPS-induced NF-κB activation and the subsequent upregulation of pro-inflammatory cytokines, including TNF-α, IL-6, IL-1β, and MCP-1. Interestingly, SPI(-) inhibited NF-κB-dependent inflammatory responses by targeting I-κB phosphorylation and AKT activation with no effect on MAP kinase pathway. Of the five putative soy peptides, four of the soy peptides inhibited LPS-induced VCAM-1, IL-6, IL-8, and MCP-1 protein expression in human vascular endothelial cells in vitro. CONCLUSIONS: Collectively, our findings suggest that anti-inflammatory properties of component(s) of soy protein/peptides may be a possible mechanism for the prevention of chronic inflammatory diseases such as atherosclerosis.