Salusin-β Not Salusin-α Promotes Vascular Inflammation in ApoE-Deficient Mice via the I-κBα/NF-κB Pathway

Objective: Vascular inflammation plays an important role in the development and progression of atherosclerosis. Recently, salusins (salusin-alpha and salusin-beta) have been reported to be associated wtih atherosclerosis. However, its underlying mechanism remains incompletely known. In this study, we observed the effects of salusins on vascular inflammation in apoE-deficient (apoE-/-) mice. Methods and Results: Six-week old male apoE-/- mice were infused with salusin-alpha, salusin-beta or vehicle for 8 weeks via osmotic mini-pumps. Our results showed that apoE-/- mice receiving vehicle alone developed severe atherosclerotic lesions and dyslipidemia, with significantly up-regulated levels of IL-6, TNF-alpha, VCAM-1 and MCP-1. For apoE-/- mice receiving 8 weeks of salusin-beta infusion, the atherosclerotic lesions were markedly aggravated, and the levels of IL-6, TNF-alpha, VCAM-1 and MCP-1 were substantially increased, despite a similar plasma lipid concentration with that of apoE-/- mice. However, after 8 week-infusion of salusin-alpha, apoE-/- mice presented significant amelioration in atherosclerotic lesions, along with remarkably up-regulated level of high-density lipoprotein-cholesterol (HDL-C) and down-regulated levels of IL-6 and TNF-alpha, but without any effect on the expressions of VCAM-1 and MCP-1. Furthermore, the activation of nuclear factor-kappa B (NF-kappa B), an important transcription factor essential for inflammatory molecules, and the degradation of I-kappa B alpha, an inhibitor of NF-kappa B, were markedly increased in apoE-/- mice receiving vehicle alone. Treatment with salusin-beta not salusin-alpha could remarkably accelerate the process of NF-kappa B nuclear translocation and I-kappa B alpha degradation. Conclusion: Salusin-beta, but not salusin-alpha, promotes vascular inflammation in apoE-deficient mice via the I-kappa B alpha/NF-kappa B pathway. These findings provide further insight into the mechanism of salusins in atherosclerosis and potential targets for the prevention and treatment of atherosclerosis.