Abstract 5849: The Effects of Statins and Prenylation Inhibitors on Chronic Rejection in Heart Transplantation

Abstract

HMG-CoA Reductase Inhibitors (statins) increase patient survival and decrease Graft Coronary Artery Disease (GCAD) in heart transplants. Although the exact mechanism is unknown, the protective role of statins may be attributed to two factors: modifications in cholesterol metabolism or small G protein prenylation, and/or immunosuppression or changes on graft endothelial cell (EC) and smooth muscle cell (SMC) function. We hypothesized that statins attenuate GCAD development through alterations in G protein prenylation primarily in graft SMC and EC. Using a murine heterotopic heart transplant model (B6 BM12 to C57BL/6), animals received no treatment (control); HMG-CoA Reductase inhibitor (Atorvastatin, AT); or drugs that selectively block the four major downstream branches of the mevalonate pathway (squalene synthase (ZA), farnesyl protein transferase (MA), geranylgeranyl protein transferase (GGPT-2) (NE), GGPT-1 and -2 (PA), and both FPT and GGPT-2 (NE+MA)). Intimal proliferation was measured with morphometric analysis. In vitro assays were utilized to determine SMC activity, T-cell function, and EC MHC-2 expression. AT, MA, and NE significantly decreased GCAD development, while ZA and NE+MA had no effect (control 63.2± 38%, AT 29.3± 37.5%, MA 43.0± 39.3%, PA 47.5+/−42.5%, NE 24.7± 37.1%, ZA 65.4± 32.5%; p< 0.01). After 5 days of therapy, ELISPOT analysis revealed that all selective inhibitors decreased the Th2 response, and all except AT decreased the Th1 response, with NE levels equivalent to syngeneic controls (p< 0.001). In vitro, inhibition with AT, PA, or NE reduced SMC proliferation and migration compared to controls (p< 0.01). IFNγ-stimulated MHC-2 expression on EC decreased with AT, PA, or NE treatment in a dose dependent manner (p< 0.01). This is the first study to evaluate the effects of prenylation inhibitors on both recipient and graft responses to heart transplantation. Our data shows that inhibition of GGPT-2, and not cholesterol synthesis, is the molecular target of statins’ attenuation of GCAD. Our data suggests that the beneficial effects seen with statin therapy after heart transplant are due to decreased T-cell function and decreased graft SMC and EC function.