Leukocyte ABCA1 impedes progression of established atherosclerotic lesions after dietary cholesterol lowering in LDLr-/- mice

Background: Impairment of cellular cholesterol trafficking is at the heart of atherosclerotic lesions formation. This involves egress of cholesterol from the lysosomes and two lysosomal proteins, the Niemann-Pick C1 (NPC1) and NPC2 that promotes cholesterol trafficking. However, movement of cholesterol out the lysosome and how disrupted cholesterol trafficking leads to atherosclerosis is unclear. As the Wnt ligand, Wnt5a inhibits the intracellular accumulation of cholesterol in multiple cell types, we tested whether Wnt5a interacts with the lysosomal cholesterol export machinery and studied its role in atherosclerotic lesions formation. Methods: We generated mice deleted for the Wnt5a gene in vascular smooth muscle cells (VSMCs). To establish whether Wnt5a also protects against cholesterol accumulation in human VSMCs, we used a CRISPR/Cas9 guided nuclease approach to generate human VSMCs knockout for Wnt5a. Results: We show that Wnt5a is a crucial component of the lysosomal cholesterol export machinery. By increasing lysosomal acid lipase expression, decreasing metabolic signaling by the mTORC1 kinase, and through binding to NPC1 and NPC2, Wnt5a senses changes in dietary cholesterol supply and promotes lysosomal cholesterol egress to the endoplasmic reticulum (ER). Consequently, loss of Wnt5a decoupled mTORC1 from variations in lysosomal sterol levels, disrupted lysosomal function, decreased cholesterol content in the ER, and promoted atherosclerosis. Conclusions: These results reveal an unexpected function of the Wnt5a pathway as essential for maintaining cholesterol homeostasis in vivo.

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Stage-Specific Remodeling of Atherosclerotic Lesions upon Cholesterol Lowering in LDL Receptor Knockout Mice

American Journal Of Pathology ◽

10.1016/j.ajpath.2011.05.020 ◽

2011 ◽

Vol 179 (3) ◽

pp. 1522-1532 ◽

Cited By ~ 11

Author(s):

Ying Zhao ◽

Dan Ye ◽

Jun Wang ◽

Laura Calpe-Berdiel ◽

Saaleha B.R.N. Azzis ◽

...

Keyword(s):

Knockout Mice ◽

Ldl Receptor ◽

Cholesterol Lowering ◽

Atherosclerotic Lesions ◽

Ldl Receptor Knockout Mice

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Effects of dietary flaxseed on vascular contractile function and atherosclerosis during prolonged hypercholesterolemia in rabbits

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01179.2005 ◽

2006 ◽

Vol 291 (6) ◽

pp. H2987-H2996 ◽

Cited By ~ 66

Author(s):

C. M. C. Dupasquier ◽

A.-M. Weber ◽

B. P. Ander ◽

P. P. Rampersad ◽

S. Steigerwald ◽

...

Keyword(s):

Vascular Function ◽

Contractile Function ◽

Plasma Cholesterol ◽

Dietary Cholesterol ◽

Relaxation Response ◽

High Cholesterol Diet ◽

Cholesterol Diet ◽

High Cholesterol ◽

Beneficial Effects ◽

Atherosclerotic Lesions

Dietary flaxseed has significant anti-atherogenic effects. However, the limits of this action and its effects on vascular contractile function are not known. We evaluated the effects of flaxseed supplementation on atherosclerosis and vascular function under prolonged hypercholesterolemic conditions in New Zealand White rabbits assigned to one of four groups for 6, 8, or 16 wk of feeding: regular diet (RG), 10% flaxseed-supplemented diet (FX), 0.5% cholesterol-supplemented diet (CH), and 0.5% cholesterol- and 10% flaxseed-supplemented diet (CF). Cholesterol feeding resulted in elevated plasma cholesterol levels and the development of atherosclerosis. The CF group had significantly less atherosclerotic lesions in the aorta and carotid arteries after 6 and 8 wk than the CH animals. However, the anti-atherogenic effect of flaxseed supplementation was completely attenuated by 16 wk. Maximal tension induced in aortic rings either by KCl or norepinephrine was not impaired by dietary cholesterol until 16 wk. This functional impairment was not prevented by including flaxseed in the high-cholesterol diet. Aortic rings from the cholesterol-fed rabbits exhibited an impaired relaxation response to acetylcholine at all time points examined. Including flaxseed in the high-cholesterol diet completely normalized the relaxation response at 6 and 8 wk and partially restored it at 16 wk. No significant changes in the relaxation response induced by sodium nitroprusside were observed in any of the groups. In summary, dietary flaxseed is a valuable strategy to limit cholesterol-induced atherogenesis as well as abnormalities in endothelial-dependent vasorelaxation. However, these beneficial effects were attenuated during prolonged hypercholesterolemic conditions.

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Estrogens and atherosclerosis: insights from animal models and cell systems

Journal of Molecular Endocrinology ◽

10.1530/jme-11-0145 ◽

2012 ◽

Vol 48 (2) ◽

pp. R13-R29 ◽

Cited By ~ 51

Author(s):

Jerzy-Roch Nofer

Keyword(s):

Animal Models ◽

Molecular Mechanisms ◽

Dietary Cholesterol ◽

Epidemiological Studies ◽

Transgenic Mouse Models ◽

Cell Systems ◽

Physiological Processes ◽

Atherosclerotic Lesions

Estrogens not only play a pivotal role in sexual development but are also involved in several physiological processes in various tissues including vasculature. While several epidemiological studies documented an inverse relationship between plasma estrogen levels and the incidence of cardiovascular disease and related it to the inhibition of atherosclerosis, an interventional trial showed an increase in cardiovascular events among postmenopausal women on estrogen treatment. The development of atherosclerotic lesions involves complex interplay between various pro- or anti-atherogenic processes that can be effectively studied onlyin vivoin appropriate animal models. With the advent of genetic engineering, transgenic mouse models of atherosclerosis have supplemented classical dietary cholesterol-induced disease models such as the cholesterol-fed rabbit. In the last two decades, these models were widely applied along within vitrocell systems to specifically investigate the influence of estrogens on the development of early and advanced atherosclerotic lesions. The present review summarizes the results of these studies and assesses their contribution toward better understanding of molecular mechanisms underlying anti- and/or pro-atherogenic effects of estrogens in humans.

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ACAT inhibitor pactimibe sulfate (CS-505) reduces and stabilizes atherosclerotic lesions by cholesterol-lowering and direct effects in apolipoprotein E-deficient mice

Atherosclerosis ◽

10.1016/j.atherosclerosis.2006.03.007 ◽

2007 ◽

Vol 190 (2) ◽

pp. 239-247 ◽

Cited By ~ 36

Author(s):

Naoki Terasaka ◽

Atsuhiro Miyazaki ◽

Naomi Kasanuki ◽

Kayoko Ito ◽

Naoko Ubukata ◽

...

Keyword(s):

Apolipoprotein E ◽

Direct Effects ◽

Cholesterol Lowering ◽

Atherosclerotic Lesions ◽

Acat Inhibitor ◽

Deficient Mice

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Dietary Cholesterol Supplements Disturb Copper Homeostasis in Multiple Organs in Rabbits: Aorta Copper Concentrations Negatively Correlate with the Severity of Atherosclerotic Lesions

Biological Trace Element Research ◽

10.1007/s12011-021-02618-0 ◽

2021 ◽

Author(s):

Hualin Li ◽

Lijun Zhao ◽

Tao Wang ◽

Y. James Kang

Keyword(s):

Dietary Cholesterol ◽

Copper Homeostasis ◽

Multiple Organs ◽

Atherosclerotic Lesions

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Atherosclerotic lesion-specific copper delivery suppresses atherosclerosis in high-cholesterol-fed rabbits

Experimental Biology and Medicine ◽

10.1177/15353702211046541 ◽

2021 ◽

pp. 153537022110465

Author(s):

Na Wang ◽

Xinwen Xu ◽

Hualin Li ◽

Qipu Feng ◽

Hongge Wang ◽

...

Keyword(s):

Dietary Cholesterol ◽

Atherosclerotic Lesion ◽

Atherosclerotic Lesions ◽

Copper Supplementation ◽

New Zealand White Rabbits ◽

Endothelial Cell Death ◽

The Stability ◽

Copper Delivery ◽

Ultrasound Sonication ◽

Progression Of Atherosclerosis

Dietary cholesterol supplements cause hypercholesterolemia and atherosclerosis along with a reduction of copper concentrations in the atherosclerotic wall in animal models. This study was to determine if target-specific copper delivery to the copper-deficient atherosclerotic wall can block the pathogenesis of atherosclerosis. Male New Zealand white rabbits, 10-weeks-old and averaged 2.0 kg, were fed a diet containing 1% (w/w) cholesterol or the same diet without cholesterol as control. Twelve weeks after the feeding, the animals were injected with copper-albumin microbubbles and subjected to ultrasound sonication specifically directed at the atherosclerotic lesions (Cu-MB-US) for target-specific copper delivery, twice a week for four weeks. This regiment was repeated 3 times with a gap of two weeks in between. Two weeks after the last treatment, the animals were harvested for analyses of serum and aortic pathological changes. Compared to controls, rabbits fed cholesterol-rich diet developed atherosclerotic lesion with a reduction in copper concentrations in the lesion tissue. Cu-MB-US treatment significantly increased copper concentrations in the lesion, and reduced the size of the lesion. Furthermore, copper repletion reduced the number of apoptotic cells as well as the content of cholesterol and phospholipids in the atherosclerotic lesion without a disturbance of the stability of the lesion. The results thus demonstrate that target-specific copper supplementation suppresses the progression of atherosclerosis at least in part through preventing endothelial cell death, thus reducing lipid infiltration in the atherosclerotic lesion.

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