Estrogen-Mediated Increases in LDL Cholesterol and Foam Cell–Containing Lesions in Human ApoB100×CETP Transgenic Mice

Zuckerman, Steven H.; Evans, Glenn F.; Schelm, J A; Eacho, Patrick I.; Sandusky, George E.

doi:10.1161/01.atv.19.6.1476

Cited by 21 publications

(15 citation statements)

References 46 publications

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“…[17] The contiguous frozen sections were stained with Movat pentachrome stain and dihydroethidium (DHE) (Sigma). Other parts of branchiocephalic arteries (BCA) were dissected and fixed overnight in 4% polymerizedformaldehyde, followed by paraffin embedded, and sectioned 5-µm-thick.…”

Section: Analysis Of the Lesions In The Branchiocephalic Artery And Tmentioning

confidence: 99%

Panax Notogingseng Saponins Suppress RAGE/ MAPK Signaling and NF-kappaB Activation in Apolipoprotein-E-deficient Atherosclerosis-prone mice

Dou

Lu²,

Shen³

et al. 2012

Cell Physiol Biochem

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Background: Panax notoginseng saponins (PNS) extracted from the roots of panax notoginseng are free radical-scavenger, with an antioxidant property, capable of inhibiting expression of adhesion molecules and chemokines. This study was designed to test the effects of PNS administration in apolipoprotein (apo)-E-deficient mice on the activation of JNK, p38^MAPK, ERK1/2 and NF-ĸB, and the expression of RAGE, adhesion molecules and chemokines in the atherosclerotic lesions. Methods: Wild type and apoE-null mice (male, 10-week-old) were treated with PNS for 4 weeks. Peripheral blood was collected for assessing the serum levels of glucose, lipids and MDA, and activities of SOD and GSH. The sizes of atherosclerotic lesions and numbers of macrophages in the branchiocephalic arteries, and the reactive oxygen species (ROS) production in the aortic root were analyzed. The levels of CD68, Galectin-3, RAGE, JNK, phosphor-JNK, p38^MAPK, phosphor-p38^MAPK, ERK1/2, phosphor-ERK1/2, I-ĸB, phosphor-I-ĸB (Ser32), NF-ĸB, phosphor-NF-ĸB, MCP-1, VCAM-1 and ICAM-1 in the descending arteries were identified by Western blot. Results: The atherosclerotic lesion sizes, and macrophage numbers, but not the smooth muscle cell amounts and the collagen content, were decreased in apoE^-/mice treated with PNS. After PNS administration for 4 weeks, the apoE^-/-mice displayed reduced level of serum MDA and enhanced activity of SOD and GSH, accompanied by impaired ROS generation in the aortic root. Moreover, PNS down-regulated the expression of VCAM-1, ICAM-1 and MCP-1, accompanied by reduced expression of RAGE and suppressed the activation of NF-ĸB, JNK, p38^MAPK and ERK1/2. Conclusion: PNS may inhibit progression of atherosclerotic lesions via their antioxidant/anti-inflammatory biological properties. PNS suppress the RAGE/MAPK signaling pathways, inactivate NF-ĸB, and reduce expression of pro-inflammatory factors, such as VCAM-1, ICAM-1 and MCP-1 in atherosclerotic lesions of apoE^-/-mice.

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Section: Analysis Of the Lesions In The Branchiocephalic Artery And Tmentioning

confidence: 99%

Panax Notogingseng Saponins Suppress RAGE/ MAPK Signaling and NF-kappaB Activation in Apolipoprotein-E-deficient Atherosclerosis-prone mice

Dou

Lu²,

Shen³

et al. 2012

Cell Physiol Biochem

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“…Estrogen deficiency per se does not alter plasma CETP activity as shown in castrated CETP transgenic mice (15). Also, estrogen therapy has no impact on the plasma CETP activity in humans (16) as well as in apolipoprotein B/CETP double transgenic mouse model (17).…”

mentioning

confidence: 94%

Cholesteryl ester transfer protein expression attenuates atherosclerosis in ovariectomized mice

Cazita

Berti

Aoki

et al. 2003

Journal of Lipid Research

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(2); however, the precise effects of CETP on atherogenesis are controversial. In humans, increased incidence of coronary heart disease has been associated with both CETP deficiency (3) and augmentation (4). In several animal models of atherosclerosis, the effects of CETP on vascular health are clearly dependent upon the metabolic context (5-11).Various researchers are attempting to target CETP as a form of therapy (9-13), but these approaches will be useless unless the circumstances where CETP acts as pro-or anti-atherogenic are properly clarified.Deficiency in endogenous estrogen accounts for the loss of protection against coronary heart disease after menopause or following bilateral ovariectomy (14). Estrogen deficiency per se does not alter plasma CETP activity as shown in castrated CETP transgenic mice (15). Also, estrogen therapy has no impact on the plasma CETP activity in humans (16) as well as in apolipoprotein B/CETP double transgenic mouse model (17).The present study aimed at investigating whether CETP expression would alter the development of atherosclerosis in a moderately hypercholesterolemic mouse model lacking ovarian hormones. For this purpose, mice expressing the human CETP gene were crossbred with LDL receptor (LDLR) knockout mice. On a high fat diet, the LDLR knockout mice develop extensive aorta atherosclerosis in a pattern similar to humans (18,19). We have shown here that the expression of the CETP gene significantly reduced the development of atherosclerotic lesions in ovariectomized hypercholesterolemic mice. Furthermore, this antiatherogenic effect of CETP was blunted by the estrogen replacement therapy.

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“…Treatment of young women (25) or hypogonadic men (42) with testosterone did not change plasma CETP activity. Similarly, estrogen deficiency (43) or estrogen therapy (44,45) had no impact on the plasma CETP activity in humans and Tg mice. Although castration did not change CETP plasma levels in female mice, we showed recently that CETP expression reduced atherosclerosis by 50% in ovariectomized Tg mice (36).…”

mentioning

confidence: 95%

Atherosclerosis is enhanced by testosterone deficiency and attenuated by CETP expression in transgenic mice

Casquero

Berti

Salerno

et al. 2006

Journal of Lipid Research

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In this work, we investigated the impact of testosterone deficiency and cholesteryl ester transfer protein (CETP) expression on lipoprotein metabolism and dietinduced atherosclerosis. CETP transgenic mice and nontransgenic (nTg) littermates were studied 4 weeks after bilateral orchidectomy or sham operation. Castrated mice had an increase in the LDL fraction (136% for CETP and 179% for nTg mice), whereas the HDL fraction was reduced (230% for CETP and 211% for nTg mice). Castrated mice presented 1.7-fold higher titers of anti-oxidized LDL (Ox-LDL) antibodies than sham-operated controls. Plasma levels of CETP, lipoprotein lipase, and hepatic lipase were not changed by castration. Kinetic studies showed no differences in VLDL secretion rate, VLDL-LDL conversion rate, or number of LDL and HDL receptors. Competition experiments showed lower affinity of LDL from castrated mice for tissue receptors. Diet-induced atherosclerosis studies showed that testosterone deficiency increased by 100%, and CETP expression reduced by 44%, the size of aortic lesion area in castrated mice. In summary, testosterone deficiency increased plasma levels of apolipoprotein B-containing lipoproteins (apoB-LPs) and anti-OxLDL antibodies, decreased LDL receptor affinity, and doubled the size of diet-induced atherosclerotic lesions. The expression of CETP led to a milder increase of apoB-LPs and reduced atherosclerotic lesion size in testosterone-deficient mice. Gender differences in coronary artery disease (CAD) risk observed during the reproductive life period have been attributed to an attenuating effect of estrogen on atherogenesis (1, 2) and/or to a proatherogenic action of androgens (3, 4). However, the unexpected outcomes from the Women's Health Initiative and Heart and Estrogen Replacement Study trials (5, 6) and other controversies about the role of androgens (7) necessitate further investigation of the role of sex steroids, especially in sexmatched individuals. Androgen's effects on lipoprotein metabolism and risk of atherosclerosis are not unequivocal (7,8). Increased endogenous serum testosterone in men has been associated with a favorable lipid profile (9, 10), and low endogenous levels of testosterone have been associated with an atherogenic lipid profile (11, 12) and CAD (13,14). However, other studies have not found such relationships (15-18). Aromatization of testosterone into 17b-estradiol seems to be an important determinant of the beneficial effects of androgens observed in men (19,20) and mice (21,22). On the other hand, increasing endogenous androgen levels in women (23, 24), androgenic supplementation in men (3), in women (25), and in female animals (26,27), and nonmedical use of androgenic anabolic steroids (4,28,29) are associated with increased risk factors for atherosclerotic diseases.Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester (CE) from HDL to apolipoprotein B-containing lipoproteins (apoB-LPs) in exchange for triglycerides (TGs), thus remodeling HDL composition in the plasma of sev...

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Estrogen-Mediated Increases in LDL Cholesterol and Foam Cell–Containing Lesions in Human ApoB100×CETP Transgenic Mice

Cited by 21 publications

References 46 publications

Panax Notogingseng Saponins Suppress RAGE/ MAPK Signaling and NF-kappaB Activation in Apolipoprotein-E-deficient Atherosclerosis-prone mice

Panax Notogingseng Saponins Suppress RAGE/ MAPK Signaling and NF-kappaB Activation in Apolipoprotein-E-deficient Atherosclerosis-prone mice

Cholesteryl ester transfer protein expression attenuates atherosclerosis in ovariectomized mice

Atherosclerosis is enhanced by testosterone deficiency and attenuated by CETP expression in transgenic mice

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