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Gene Inactivation of Proprotein Convertase Subtilisin/Kexin Type 9 Reduces Atherosclerosis in Mice
Abstract
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.
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Knockout of PCSK9 reduced cholesteryl ester accumulated in the aortas of apoE−/− mice by ~39%, even though the sizes of the entire lesions were not significantly altered.
“Denis et al. reported that knockout of PCSK9 reduced cholesteryl ester accumulated in the aortas of apoE−/− mice by ~39%, even though the sizes of the entire lesions were not significantly altered28.”
From Membrane type 1 matrix metalloproteinase promotes LDL receptor shedding and accelerates the development of atherosclerosis (2021) · cites this paper as [28]
Overexpression of PCSK9 enhances the development of atherosclerosis and knockout of PCSK9 reduces the levels of aortic cholesterol in apoE−/− mice.
“It has been reported that overexpression of PCSK9 enhances the development of atherosclerosis and knockout of PCSK9 reduces the levels of aortic cholesterol in apoE−/− mice 28.”
From Membrane type 1 matrix metalloproteinase promotes LDL receptor shedding and accelerates the development of atherosclerosis (2021) · cites this paper as [28]
Knockout of PCSK9 in apoE−/− mice did not significantly affect plasma cholesterol levels or atherosclerotic plaque sizes despite increased hepatic LDLR levels.
“This was similar to a phenotype reported in the study of PCSK9 that knockout of PCSK9 in apoE−/− mice did not significantly affect plasma cholesterol levels or atherosclerotic plaque sizes despite of increased hepatic LDLR levels28.”
From Membrane type 1 matrix metalloproteinase promotes LDL receptor shedding and accelerates the development of atherosclerosis (2021) · cites this paper as [28]
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Metadata
- Authors
- Denis, M., Marcinkiewicz, J., Zaid, A., Gauthier, D., Poirier, S., Lazure, C., Seidah, N. G., & Prat, A.
- Venue
- Circulation
- Published
- 2012-02-21
- Volume
- 125
- Issue
- 7
- Pages
- 894-901
- ISSN
- 0009-7322
- 1524-4539
- Cited by
- 212
- References
- 5
- Language
- en
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