The proliferation of vascular smooth muscle cells (VSMCs) induced by oxidative injury is one of the main features in diabetes-accelerated
atherosclerosis. Geranylgeranyl
transferase-I (
GGTase-I) is an essential
enzyme mediating posttranslational modification, especially the geranylgeranylation of
small GTPase, Rac1. Our previous studies found that
GGTase-I played an important role in diabetes-accelerated
atherosclerosis. However, its exact role is largely unclear. In this study, mouse conditional knockout of VSMC
GGTase-I (Pggt1b Δ/Δ mice) was generated using the CRISPR/Cas9 system. The mouse model of diabetes-accelerated
atherosclerosis was induced by
streptozotocin injections and an atherogenic diet. We found that
GGTase-I knockout attenuated diabetes-accelerated
atherosclerosis in vivo and suppressed high-
glucose-induced VSMC proliferation in vitro. Moreover, after a 16-week duration of diabetes, Pggt1b Δ/Δ mice exhibited lower α-smooth muscle actin (α-SMA) and
nitrotyrosine level, Rac1 activity, p47phox and NOXO1 expression, and phospho-ERK1/2 and phosphor-JNK content than wild-type mice. Meanwhile, the same changes were found in Pggt1b Δ/Δ VSMCs cultured with high
glucose (22.2 mM) in vitro. In conclusion,
GGTase-I knockout efficiently blocked diabetes-accelerated
atherosclerosis, and this protective effect must be related to the inhibition of VSMC proliferation. The potential mechanisms probably involved interfering Rac1 geranylgeranylation, inhibiting the assembly of
NADPH oxidase cytosolic regulatory subunits, reducing oxidative injury, and decreasing ERK1/2 and JNK phosphorylation.