scholarly journals Pleiotropic Effects of Atorvastatin Result in a Downregulation of the Carboxypeptidase U System (CPU, TAFIa, CPB2) in a Mouse Model of Advanced Atherosclerosis

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1731
Author(s):  
Karen Claesen ◽  
Lynn Roth ◽  
Joachim C. Mertens ◽  
Karlijn Hermans ◽  
Yani Sim ◽  
...  
Keyword(s):  
Plasma Cholesterol ◽  
Statin Treatment ◽  
Pleiotropic Effect ◽  
Heterozygous Mutation ◽  
Total Plasma Cholesterol ◽  
Total Plasma ◽  
Atorvastatin Group ◽  
Reductase Inhibitors ◽  
Cholesterol Levels ◽  
Fibrillin 1

Statins (hydroxymethyl-glutaryl-CoA-reductase inhibitors) lower procarboxypeptidase U (proCPU, TAFI, proCPB2). However, it is challenging to prove whether this is a lipid or non-lipid-related pleiotropic effect, since statin treatment decreases cholesterol levels in humans. In apolipoprotein E-deficient mice with a heterozygous mutation in the fibrillin-1 gene (ApoE−/−Fbn1C1039G+/−), a model of advanced atherosclerosis, statins do not lower cholesterol. Consequently, studying cholesterol-independent effects of statins can be achieved more straightforwardly in these mice. Female ApoE −/−Fbn1C1039G+/− mice were fed a Western diet (WD). At week 10 of WD, mice were divided into a WD group (receiving WD only) and a WD + atorvastatin group (receiving 10 mg/kg/day atorvastatin +WD) group. After 15 weeks, blood was collected from the retro-orbital plexus, and the mice were sacrificed. Total plasma cholesterol and C-reactive protein (CRP) were measured with commercially available kits. Plasma proCPU levels were determined with an activity-based assay. Total plasma cholesterol levels were not significantly different between both groups, while proCPU levels were significantly lower in the WD + atorvastatin group. Interestingly proCPU levels correlated with CRP and circulating monocytes. In conclusion, our results confirm that atorvastatin downregulates proCPU levels in ApoE−/−Fbn1C1039G+/− mice on a WD, and evidence was provided that this downregulation is a pleiotropic effect of atorvastatin treatment.

scholarly journals Candidate Gene Test for Quantitative Trait Loci Conferring Hypercholesterolemia on Mouse Chromosome 1

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 942-942
Author(s):  
Jung Han Kim ◽  
Jacaline Parkman ◽  
Kristiana Sklioutovskaya-Lopez
Keyword(s):  
Quantitative Trait Loci ◽  
Quantitative Trait ◽  
Significant Interaction ◽  
Plasma Cholesterol ◽  
Complementation Test ◽  
Total Plasma Cholesterol ◽  
Total Plasma ◽  
Cholesterol Levels ◽  
Trait Loci ◽  
Main Effects

Abstract Objectives The TALLYHO (TH) mouse is a polygenic model for obesity, type 2 diabetes and hyperlipidemia. We previously established a subcongenic mouse with TH donor segment, ∼25 Mb, on chromosome (Chr) 1 in a C57BL/6J (B6) background that harbors quantitative trait loci (QTL) conferring hypercholesterolemia, named Tchol1 (Tallyho Associated Cholesterol 1). The subcongenic mouse developed hypercholesterolemia compared to B6 mice demonstrating that distal segment of Chr 1 from TH genome is necessary to cause the hypercholesterolemia. In this study, we tested the candidacy of the apolipoprotein A2 (Apoa2) gene for Tachol1 by the quantitative complementation test. Apoa2, known regulator of cholesterol metabolism, maps to the Tchol1 locus. Methods To carry out the quantitative complementation test, both TH-homozygous Tachol1 subcongenic and B6-homozygous (B6) mice were mated to the Apoa2 knockout heterozygous [wild-type (wt)/null] mice to produce four types of animals; TH/wt, TH/null, B6/wt, and B6/null. Both male and female mice were weaned onto standard rodent chow and maintained. Blood was collected when animals were euthanized at 16 weeks of age. Total plasma cholesterol levels were determined using colorimetric assays. A two-way ANOVA was used to evaluate Apoa2 (null vs. wt) and Tachol1 (TH vs. B6) interaction effects for dependent variables, followed by the multiple comparison post test with Tukey correction using GraphPad Prism 8. Results Total plasma cholesterol levels were: 137 ± 5 (TH/wt), 119 ± 8 (TH/null), 103 ± 8 (B6/wt), and 80 ± 4 (B6/null) for males, and 149 ± 8 (TH/wt), 130 ± 9 (TH/null), 98 ± 3 (B6/wt), and 103 ± 6 (B6/null) for females [mean ± s.e.m; mg/dl]. Two-way ANOVA revealed no significant interaction between Tchol1 and Apoa2 knockout alleles for total plasma cholesterol levels in both males and females. However, there were significant main effects of Tchol1 and Apoa2 knockout alleles on total plasma cholesterol levels in males, while significant main effects of Tchol1 on them in females. Conclusions No significant interaction effect between knockout and QTL alleles is interpreted as evidence that the knockout locus is not equal to the QTL. Our results suggest that the Apoa2 gene is not identical to the Tchol1 QTL. Funding Sources AHA 18AIREA33960437, NIH 1 R15 DK113604-01A1, the WV-INBRE grant (P20GM103434), and the COBRE ACCORD grant (1P20GM121299).

The prevalence of subclinical hypothyroidism at different total plasma cholesterol levels in middle aged men and women: a need for case-finding?

1999 ◽  
Vol 50 (2) ◽  
pp. 217-220 ◽  
Author(s):  
Alexander J. G. H. Bindels ◽  
Rudi G. J. Westendorp ◽  
Marijke Frölich ◽  
Jacob C. Seidell ◽  
Anneke Blokstra ◽  
...  
Keyword(s):  
Subclinical Hypothyroidism ◽  
Plasma Cholesterol ◽  
Case Finding ◽  
Total Plasma Cholesterol ◽  
Total Plasma ◽  
Middle Aged ◽  
Men And Women ◽  
Cholesterol Levels

Total plasma cholesterol levels of rats are increased following only three sessions of tailshock

Life Sciences ◽  
1992 ◽  
Vol 50 (13) ◽  
pp. 945-950 ◽  
Author(s):  
Francis X. Brennan ◽  
R.F. Soames Job ◽  
Linda R. Watkins ◽  
Steven F. Maier
Keyword(s):  
Plasma Cholesterol ◽  
Total Plasma Cholesterol ◽  
Total Plasma ◽  
Cholesterol Levels

scholarly journals Development of Lipid and Glycide Abnormalities in Genetically Hypertensive Obese Koletsky Rats and in Their Lean Siblings

1998 ◽  
Vol 41 (4) ◽  
pp. 163-166
Author(s):  
Věroslav Golda ◽  
Jiřina Hilgertová
Keyword(s):  
Body Weight ◽  
Glucose Intolerance ◽  
Plasma Cholesterol ◽  
The Body ◽  
Total Plasma Cholesterol ◽  
Total Plasma ◽  
Plasma Triglycerides ◽  
Obese Rats ◽  
Lipid Abnormalities ◽  
Genetically Hypertensive

Experiments were performed in the genetically hypertensive Koletsky rats and in their lean siblings at the age of two and three months. In the study of development of glycide and lipid abnormalities animal represents control for itself. At the age of two months Koletsky obese rats show relative to their lean controls elevation of plasma triglycerides (males +184%, females +152%) and insulin (males +169%, females +201%). During one month plasma triglycerides elevated in lean males +9%, in lean females 0%, but in obese males +21%, in obese females +139%.Considering insulinemia similar results were obtained. Thus during one month insulin elevates in lean males +19%, in lean females +23%, but in obese males +80%, in obese females +144%. During one month glucose intolerance is elevated as well only in obese rats. Total plasma cholesterol during period of one month shows no changes in both substrains of rats.Similar picture can be found in basal glycemia.In all groups of rats no changes were registered except one, i.e., obese females show decrease.Considering the substrain differences in basal glycemia then at age of one as well as two months obese of both sexes show elevation. As to the body weight at the age of two as well as three months there is increase in obese rats. The changes of body weight during one month are expressively higher in obese rats.

Cholesterol feeding exacerbates myocardial injury in Zucker diabetic fatty rats

2000 ◽  
Vol 278 (1) ◽  
pp. H256-H262 ◽  
Author(s):  
Shiro Hoshida ◽  
Nobushige Yamashita ◽  
Kinya Otsu ◽  
Tsunehiko Kuzuya ◽  
Masatsugu Hori
Keyword(s):  
Infarct Size ◽  
Myocardial Injury ◽  
Coronary Occlusion ◽  
Plasma Cholesterol ◽  
Diabetic Rats ◽  
Total Plasma Cholesterol ◽  
Total Plasma ◽  
Cholesterol Feeding ◽  
Insulin Dependent ◽  
Zdf Rats

We measured infarct size after coronary occlusion (30 min) and reperfusion (24 h) in genetic non-insulin-dependent Zucker diabetic fatty (ZDF) rats with and without 4-wk cholesterol feeding. Infarct size was similar in ZDF rats and lean control rats but was significantly larger in cholesterol-fed diabetic rats than in cholesterol-fed lean rats ( P < 0.05). Plasma levels of glucose, insulin, and triglycerides were significantly higher in diabetic rats and were not influenced by cholesterol feeding. The increase in total plasma cholesterol induced by cholesterol feeding was significantly greater in diabetic rats than in lean rats ( P < 0.05). A significant positive correlation was found between total plasma cholesterol and infarct size ( P < 0.05). Myeloperoxidase activity, as an index of neutrophil accumulation, was significantly higher and expression of P-selectin was more marked in the ischemic myocardium of cholesterol-fed diabetic rats than of cholesterol-fed lean rats. Acetylcholine-induced endothelium-dependent relaxation (EDR) of aortic rings was markedly impaired in cholesterol-fed diabetic rats. Thus cholesterol feeding significantly exacerbated myocardial injury produced by coronary occlusion-reperfusion in non-insulin-dependent diabetic rats, possibly because of enhanced expression of P-selectin and impairment of EDR in the coronary bed.

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