Low-dose oral cyclophosphamide therapy reduces atherosclerosis progression by decreasing inflammatory cells in a murine model of atherosclerosis

BACKGROUND: Atherosclerosis is a chronic inflammatory disease responsible for most cases of heart disease and stroke in Western countries. The cytotoxic drug cyclophosphamide (CPA) can modulate immune functions, and it has therefore been used to treat patients with autoimmune diseases. Extension of survival of patients with severe atherosclerosis has been reported after CPA treatment, but the underlying mechanism is still poorly understood. METHODS AND RESULTS: We have investigated the effects of CPA in a murine model of atherosclerosis. Continuous oral administration of low-dose CPA (20 mg/kg/day) prevented atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice fed with a high fat diet. After 12 weeks, CPA treatment delayed progression of atherosclerosis in the mice (9.92% vs 3.32%, P < 0.05, n = 7) and reduced the macrophage content of plaques (1.228 vs 0.2975 mm(2), P < 0.001). Flow cytometry (FACS) showed that, in peripheral blood and spleen cells, the numbers of B cells and inflammatory T cells (Th1 cells) decreased, and inflammatory monocytes also decreased. However, there were no differences in the bone marrow cells between the two groups. The mRNA levels in the aorta showed significantly decreased inflammatory cytokine (interleukin-6) (P < 0.05), and tended to increase anti-inflammatory cytokine (argininase-1), but no significant differences between the two groups. High dose CPA has cardiotoxicity, but the dose used in this study did not show significant cardiotoxicity. CONCLUSIONS: The results demonstrate that oral treatment with CPA inhibits initiation and progression of atherosclerosis in the apoE(-/-) mouse model through immunomodulatory effects on lymphoid and inflammatory cells.