Abstract 12529: Low Dose Oral Cyclophosphamide Therapy Reduces Atherosclerosis Progression and Promotes Plaque Stability in a Murine Model of Atherosclerosis

Abstract

Introduction: Atherosclerosis is a chronic inflammatory disease and the primary cause of heart disease and stroke in Western countries. The cytotoxic drug cyclophosphamide (CPA) can modulate immune functions. Extended survival of patients with severe atherosclerosis has been reported after CPA treatment, but the underlying mechanism is still poorly understood. The objective of this study was to examine the antiatherosclerotic effects of CPA and the underlying mechanism in a murine model of atherosclerosis. Hypothesis: CPA treatment can alter inflammatory processes pivotal for the development of atherosclerosis, therefore limiting disease progression. Method: Apolipoprotein E deficient (ApoE-/-) mice fed a high fat diet received CPA resuspended in drinking water (37.5 g/kg /day p.o.) or water for 12 weeks, respectively. In an interventional protocol, mice fed a high fat diet received the same dose of CPA or water from week 14 to 18, respectively. Mice were sacrificed at week 12, 14 and 18, and aorta, peripheral blood cells, spleen cells and peritoneal cells of treated mice were analysed using histological methods and FACS analysis. Result: In a preventive protocol, continuous oral administration of low-dose CPA prevented disease initiation in ApoE-/- mice fed with a high fat diet. Encouraged by these data we treated mice with pre-established atherosclerosis for 4 weeks with CPA, in an interventional protocol. CPA treatment delayed disease progression in mice with advanced atherosclerosis and reduced the macrophage infiltration in plaques. Importantly, improved plaque stability with a thicker fibrous cap, and an increase in collagen deposition and decreased matrix metalloproteinase-2 and -9 expression, and a reduction of classical inflammatory macrophage (M1) numbers was observed. In addition, CPA treatment reduced the numbers of IFN-γ-producing TH1, but not TH2 lymphocytes in vivo. Conclution: Our data demonstrate that oral treatment with CPA inhibits atherosclerosis initiation and progression in ApoE-/- mouse model, through pleiotropic immunomodulatory effects on lymphoid and myeloid cells. Thus, CPA may be a valuable drug for treating advanced atherosclerosis.