Background Cluster of differentiation 40
ligand (
CD40L) and
rosuvastatin (RSV) affect
atherosclerotic plaque stability, but little is known about their roles in extracellular matrix (ECM) production. We investigated the effects of
CD40L and RSV on pre-existing advanced plaques. Methods and results Pre-existing advanced plaques were induced in
apolipoprotein E-knockout (
ApoE-/-) mice by the surgical placement of carotid constrictive
silastic collars. Two weeks after surgery, mice were divided into the following treatment groups: control, empty adenovirus,
CD40L adenovirus,
CD40L adenovirus + RSV, and RSV. Mice received adenovirus via two tail-vein
injections (2 × 109 pfu each) and/or RSV via intragastric administration (5 mg/kg; daily for 4 weeks). Mice in the
CD40L adenovirus group exhibited increased plaque disruption rates, increased relative plaque macrophage and
lipid content, reduced plaque
collagen content, and increased local
inflammation compared to the other treatment groups, but no significant differences in plaque area were observed among the groups. Notably, in the
atherosclerotic plaques of the
CD40L adenovirus group, both the
mRNA and
protein expression of prolyl-4-hydroxylase alpha 1 (P4Hα1) was significantly decreased, leading to a consequent decrease in the
protein expression of
collagen types I and III. Treatment with RSV decreased the serum levels of
CD40L in a
lipid-independent fashion and attenuated the effects of
CD40L overexpression, particularly with respect to P4Hα1 downregulation. Conclusions
CD40L destabilized advanced plaques in the carotid arteries of
ApoE-/- mice, in part by decreasing P4Hα1 expression, and consequently
collagen expression. These destabilizing effects were attenuated by RSV.