Fig. 2

Low doses of statins (left-top) potentiate HO-1 activity via PI3K/Akt. In addition, PI3K/Akt stimulates eNOS, thereby causing increased catalase activity which prevents free radical-induced senescence. Moreover, eNOS upregulates VEGF, which is a main angiogenic factor. Low doses of statins induce cell cycle progression and reduce senescence by regulating the expression of several proteins including p27Kip1. They also activate caMKKβ which drives the activation of AMPK and LKB1. In addition, by virtue of its ability to stimulate Rac 1, AMPK can also regulate NAPDH oxidase and eNOS-mediated angiogenesis. An alternative pathway by which low doses of statins induce Rac-1 is by inhibiting Rho. On the other hand, high doses (top-right) induce apoptosis by inhibiting PI3K/Akt-modulated activity of death inhibitory protein (DIP) and BAX. Moreover, statins at high concentrations, can also induce apoptosis by inhibiting Rho-induced Bcl-2 or TNF-α-induced NFkB