Abstract 9885: Exercise Enhances Vascular Protective Effects of HMG-CoA Inhibitor Statins in Mice at Advanced Age

Abstract

Introduction: Regulatory T cells (Treg) have been shown to be immune suppressors of inflammatory actions. Given that exercise or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, protect vascular tissue to stress in young animals and humans, we aimed to clarify the potential effect of swimming training (ST) to enhance the beneficial effects of statins and the cellular mechanism of the effect of statins on vascular actions in response to ischemia in mice at advanced age. Methods and Results: Aged (24 months) mice underwent hindlimb ischemic surgery. On operative day 1, the mice were randomly assigned to three groups treated with either vehicle, pitavastatin (PiS: 1 mg/kg/day; given by oral gavage every day), or PiS with swimming training (PiS-ST 1 hour/day) for 14 days. PiS treatment increased the levels of GATA3 and p-GATA6 proteins and interleukin-10 and CD206 (M2 macrophage marker) genes, whereas it suppressed the levels of p-STAT4 and tumor necrosis factor-1α proteins and C-X-C motif chemokine 10, monocyte chemotactic protein-1, gp91phox and CD40 (M1 macrophage marker) genes as well as macrophage infiltration of the ischemic muscles. PiS also reduced circulating numbers of CD4+ and CD8+ T cells and enhanced circulating CD4+/CD25+ T cells and CD31+/c-Kit+ EPCs. Moreover, EC apoptosis of the ischemic muscles ware lower in PiS-treated mice than in that of control mice. PiS improved blood flow recovery and capillary density. Interestingly, ST was found to enhance PiS-mediated beneficial actions. Conclusion: The statin-mediated beneficial effects are likely attributable, at least in part, to improvement of Treg-mediated inflammation and immune action and EC apoptosis; in addition, ST appears to enhance the vasculoprotective effects of statins, suggesting that a combination of statin and ST could be effective for the clinical treatment of cardiovascular disease in advanced age.