Endogenous FOXO3a inhibitors are also reduced in atherosclerosis and plaque VSMCs, including Akt13–15 and the deacetylase sirtuin 1.33,34 Indeed, VSMC-specific SIRT1 deletion promotes atherosclerosis, VSMC apoptosis, and marked medial degeneration, elastin breaks and aneurysm formation in mice.34 The combination of reduced FOXO3a inhibitors, increased MMP activation, and reduced TIMP expression induced by FOXO3a would have profound effects on ECM integrity in atherosclerosis in vivo. The gene discussed is SIRT1; the disease is atherosclerosis.