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

Abstract

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...

Overexpression of apolipoprotein CIII increases and CETP reverses diet-induced obesity in transgenic mice

“…22,23 In addition, CETP expression stimulates the selective uptake of HDL-derived cholesteryl ester by the liver and other tissues 24 and by human adipocytes 25,26 and protects against atherosclerosis in specific conditions such as hypertriglyceridemia 27 and sexhormone deficiency. 28,29 By reducing HDL cholesterol levels, CETP has been considered a major target for developing inhibitors aimed at reducing atherosclerosis risk (for review see Clark 30 ). However, unexpected negative outcomes from large-scale clinical trial testing the CETP-inhibitor torcetrapib have seriously questioned this strategy.…”

The low density lipoprotein receptor modulates the effects of hypogonadism on diet-induced obesity and related metabolic perturbations

“…An interesting qualitative difference in plasma lipoproteins is that castrated Ldlr Ϫ / Ϫ mice had increased levels of esterifi ed cholesterol in plasma, a fi nding that may be due to enhanced Lcat activity under conditions of hypogonadism in these mice. Work by Casquero and coworkers ( 52 ) indicated that overexpression of human cholesteryl ester transfer protein (hCetp) in mice results in a signifi cant attenuation of the increase in atherosclerosis, following surgical castration. However, these authors reported no signifi cant difference in the body weight gain of the castrated hCetp-expressing mice compared with the non-hCetp-expressing castrated littermates.…”

Is Cholesteryl Ester Transfer Protein Inhibition an Effective Strategy to Reduce Cardiovascular Risk?

“…In other studies, expression of the CETP gene has been reported to have an antiatherogenic effect in db/db obese diabetic mice, 20 in lCAT transgenic mice, 21 in ovariectomized mice, 22 in testosterone-deficient mice, 23 and in apoC-III transgenic mice with hypertriglyceridemia. 24 In the last study, however, it was also reported that expression of the Cetp gene was proatherogenic in Figure 1.…”

“…Mice fed an atherogenic diet 14 ApoE knockout mice 15 LDL receptor knockout mice 15 ApoC-III transgenic mice with normal plasma triglyceride levels 24 ApoE3-Leiden mice 16 Aypertensive rats 17 Expression of CETP in rodents had no effect on atherosclerosis SR-B1 knockout mice 18 Expression of CETP in rodents decreased atherosclerosis db/db obese, diabetic mice 20 LCAT transgenic mice 21 Ovariectomized mice 22 Testosterone-deficient mice 23 ApoC-III transgenic mice with hypertriglyceridemia 24 B. Rabbits (rabbits have a high natural level of CETP activity) Inhibition of CETP in rabbits decreased susceptibility to diet-induced atherosclerosis in:…”