Gene Inactivation of PCSK9 Reduces Atherosclerosis in Mice
Background—The proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes independently of its enzymatic activity the degradation of the LDL receptor (LDLR). 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 (apoE)-deficient and LDLR-deficient mouse models. Circulating cholesterol levels, FPLC profiles, aortic cholesteryl esters (CE) and plaque size were determined. Intima-media thicknesses were measured by ultrasound biomicroscopy. First, mice expressing null (KO), normal (WT) or high (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 apoE-deficient mice, known to spontaneously develop lesions, that expressed null (KO/e), normal (WT/e) or high (Tg/e) levels of PCSK9. Following a 6 month-regular diet, KO/e mice showed a 39% reduction compared to WT/e mice in aortic CE accumulation, while Tg/e mice showed a 137% increase. Finally, LDLR-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 similar levels of plasma cholesterol and CE accumulation to WT/L, suggesting that PCSK9 modulates atherosclerosis mainly via the LDLR.
Conclusions—Altogether, our results show a direct relationship between PCSK9 and atherosclerosis. PCSK9 overexpression is pro-atherogenic, while its absence is protective.
- Received July 25, 2011.
- Accepted December 28, 2011.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited