Increased plasma non-esterified fatty acids and platelet-activating factor acetylhydrolase are associated with susceptibility to atherosclerosis in mice.
Animal models provide vital tools to explicate the pathogenesis of atherosclerosis. Accordingly, we established two atherosclerosis-prone mice models: (i) mice lacking the LDL (low-density lipoprotein) receptor (LDLR) and the ability to edit apo (apolipoprotein) B mRNA (Apobec1; designated LDb : LDLR-/- Apobec1-/-), and (ii) mice with the LDb background, who also overexpressed human apoB100 (designated LTp : LDLR-/- Apobec1-/- ERhB+/+). Both LDb and LTp mice had markedly elevated levels of LDL and increased levels of NEFAs (non-esterified fatty acids) compared with C57BL/6 wild-type mice. However, fasting glucose and insulin levels in both animals were not different than those in C57BL/6 wild-type mice. It has been suggested that PAF-AH (platelet-activating factor acetylhydrolase) increases susceptibility to vascular disease. Both LDb and LTp mice had significantly higher PAF-AH mRNA levels compared with C57BL/6 wild-type mice. PAF-AH gene expression was also significantly influenced by age and sex. Interestingly, PAF-AH mRNA levels were significantly higher in both LTp male and female mice than in the LDb mice. This increased PAF-AH gene expression was associated with elevated plasma PAF-AH enzyme activities ( LTp > LDb > C57BL/6 ). Moreover, a greater proportion of PAF-AH activity was associated with the apoB-containing lipoproteins: 29% in LTp and 13% in LDb mice compared with C57BL/6 wild-type animals (6.7%). This may explain why LTp mice developed more atherosclerotic lesions than LDb mice by 8 months of age. In summary, increased plasma NEFAs, PAF-AH mRNA and enzyme activities are associated with accelerated atherogenesis in these animal models.
Singh
Uma
U
Research Center for Human Genetics, Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, 2121 W. Holcombe Blvd, Houston, TX 77030, USA.
Zhong
Shumei
S
Xiong
Momiao
M
Li
Tong-Bin
TB
Sniderman
Allan
A
Teng
Ba-Bie
BB
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000032:analysis*; D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics; D001161:Arteriosclerosis / Q000097:blood* / Q000235:genetics; D004198:Disease Susceptibility; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D023421:Models, Animal; D011973:Receptors, LDL / Q000235:genetics; D012306:Risk
D001055:Apolipoproteins B; D005230:Fatty Acids, Nonesterified; D011973:Receptors, LDL; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase