Gene Inactivation of Proprotein Convertase Subtilisin/Kexin Type 9 Reduces Atherosclerosis in Mice
Background The proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes independently of its enzymatic activity the degradation of the low density lipoprotein (LDL) receptor. PCSK9 gain of function in humans leads to autosomal dominant hypercholesterolemia, whereas the absence of functional PCSK9 results in 7 fold lower levels of LDL cholesterol. This suggests that lowering PCSK9 may protect against atherosclerosis. Methods and Results We investigated the role of PCSK9 in atherosclerosis in C57BL/6 wild type (WT) apolipoprotein E deficient, and LDL receptor deficient mouse models. Circulating cholesterol levels, fast protein liquid chromatography profiles, aortic cholesteryl esters (CE) and plaque sizes were determined. Intima media thicknesses were measured by ultrasound biomicroscopy. First, mice expressing null (knockout [KO] normal (WT) or high (transgenic [Tg] levels of PCSK9 were fed a 12 month Western diet. KO mice accumulated 4 fold less aortic CE than WT mice, whereas Tg mice exhibited high CE and severe aortic lesions. Next we generated apolipoprotein E deficient mice, known to spontaneously develop lesions, that expressed null (KO/e) normal (WT/e) or high (Tg/e) levels of PCSK9. After a 6 month regular diet, KO/e mice showed a 39% reduction compared with WT/e mice in aortic CE accumulation, whereas Tg/e mice showed a 137% increase. Finally, LDL receptor deficient mice expressing no (KO/L) normal (WT/L) or high (Tg/L) levels of PCSK9 were fed a Western diet for 3 months. KO/L and Tg/L mice exhibited levels of plasma cholesterol and CE accumulation similar to those of WT/L mice, suggesting that PCSK9 modulates atherosclerosis mainly via the LDL receptor. Conclusions Altogether, our results show a direct relationship between PCSK9 and atherosclerosis. PCSK9 overexpression is proatherogenic, whereas its absence is protective.
Circulation