Atherosclerosis is enhanced by testosterone deficiency and attenuated by CETP expression in transgenic mice.
In this work, we investigated the impact of testosterone deficiency and cholesteryl ester transfer protein (CETP) expression on lipoprotein metabolism and diet-induced 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 (+36% for CETP and +79% for nTg mice), whereas the HDL fraction was reduced (-30% for CETP and -11% 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.
Casquero
A C
AC
Departamento de Fisiologia e Biofísica, Instituto de Biologia, Universidade Estadual de Campinas, Sao Paulo, Brazil.
Berti
J A
JA
Salerno
A G
AG
Bighetti
E J B
EJ
Cazita
P M
PM
Ketelhuth
D F J
DF
Gidlund
M
M
Oliveira
H C F
HC
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins; D004036:Diet, Atherogenic; D015870:Gene Expression; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009919:Orchiectomy; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013739:Testosterone / Q000172:deficiency*
C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D006023:Glycoproteins; D008055:Lipids; D008074:Lipoproteins; D011994:Recombinant Proteins; D013739:Testosterone