Critical role of TNF inhibition in combination therapy for elderly mice with atherosclerosis

Aims: We have previously shown that the combination of pravastatin and sarpogrelate is synergistically beneficial for atherosclerosis. In this study, we investigated whether the pravastatin-sarpogrelate combination was sufficient for treatment in an old mouse model of atherosclerosis or if additional intervention would be needed to address the newly included aging factor and its complex pathophysiological impact on the atherosclerogenic state. We added an anti-TNF biological to the combination treatment cocktail because of the known pathologic roles of TNF in the aging process. Methods: Sixty-week-old low-density lipoprotein receptor knockout mice were fed a high-fat, high-cholesterol diet and treated with the sarpogrelate and pravastatin combination, etanercept alone, or the triple combination. Results: Although, etanercept alone did not significantly reduce aortic root and atherosclerotic plaque areas, the pravastatin-sarpogrelate combination, and pravastatin-sarpogrelate-etanercept triple therapy significantly reduced the plaque areas. Surprisingly, TNF inhibition was critically required to reduce the plaque areas of aortic roots and the expression of ICAM-1, MOMA-2, and TNF. More importantly, a lipid-lowering effect by pravastatin was observed only in the triple therapy group and not in the pravastatin and sarpogrelate combination group. Conclusions: These results suggest that TNF-inhibitory intervention should be added to the conventional therapy as a novel strategy for treating the elderly patients with atherosclerosis.