Cardiovascular disease in the JCR:LA-cp rat

The JCR:LA-cp rat is one of a number of strains that carry the mutant autosomal recessive cp gene. Animals, of all strains, that are homozygous, for the gene (cp/cp) become obese, insulin resistant, and hypertriglyceridemic. Heterozygotes or homozygous normal rats (+/+)are lean and metabolically normal. The JCR:LA-cp rat is unique in the development of a frank vasculopathy with atherosclerotic lesions and associated ischemic myocardial lesions. The cardiovascular disease is strongly correlated with the hyperinsulinemia, which develops as the animals mature from 4 to 8 weeks of age. The hyperinsulinemia can be decreased by marked food restriction, ethanol consumption, or reduction of the postprandial glucose and insulin responses through the use of a-glucosidase inhibitors. Any treatment that reduces plasma insulin levels is associated with a reduction in cardiovascular disease. In contrast, a reduction in plasma triglyceride concentrations, alone, has no effect on end-stage lesions. JCR:LA-cp rats, particularly those that are cp/cp, are, however, sensitive to cholesterol in the diet, unlike other strains that are highly resistant. Further, the rats have abnormal vascular smooth muscle cells that, especially in the cp/cp animals, are hyperplastic and activated and migrate into the intimal space. Our findings suggest that susceptibility to cardiovascular disease requires hypermsulinemic stress coupled with excessive dietary intake and the presence of one or more other necessary, but not sufficient, genetic factors. One of these may be a genetic abnormality of vascular smooth muscle cells. A similar situation may occur in humans.     

Antidiabetic properties of aqueous and methanol extracts from the trunk bark of Ceiba pentandra in type 2 diabetic rat

The type 2 diabetes is one of the major global health issues that affects millions of people. This study evaluated the antidiabetic activity of aqueous extracts (AECP) and methanol extracts (MECP) from Ceiba pentandra trunk bark on an experimental model of type 2 diabetes (T2D). This model was induced in rats by the combination of a high-fat diet (HFD) and a single dose of streptozotocin (40 mg/kg, intraperitoneal) at the seventh day of experimentation. Diabetes was confirmed on day 10 by fasting blood glucose more than or equal to 200 mg/dL. Diabetic animals still under HFD were treated orally and twice daily, with MECP and AECP (75 and 150 mg/kg) or metformin (40 mg/kg) for 14 days. During the experiment, blood glucose and animal weights were determined. Oral glucose tolerance test was performed on day 15, followed by animals sacrifice for blood, liver, and pancreas collection. Total cholesterol and triglyceride levels were evaluated in plasma, whereas malondialdehyde (MDA), glutathione (GSH), superoxide dismutase, and catalase were quantified in tissue homogenates. AECP and MECP significantly reduced the hyperglycemia by up to 62% and significantly improved the oral glucose tolerance test. The impaired levels of cholesterol and triglycerides registered in diabetic control were significantly reversed by both extracts at all the doses used. Alterations in diabetic pancreas weight, GSH, and MDA were also significantly reversed by plant extracts. AECP and MECP possess type 2 antidiabetic effects that could result from their ability to improve the peripheral use of glucose, lipid metabolism or from their capacity to reduce oxidative stress. These finding provide a new avenue for better control and management of early or advanced T2D.     

Responses of Serum Lipids and Adipose Tissue Lipases to Lipopolysaccharide Administration in Normal and Hepatoma-bearing Rats

The effects of in vivo lipopolysaccharide administration on serum lipid metabolism were studied in normal and hepatoma-bearing rats. Changes in serum lipid levels and adipose tissue lipase (lipoprotein lipase and hormone-sensitive lipase) activities following injection of lipopolysaccharide into normal rats resembled those in hepatoma- bearing rats. These results suggest the presence of some common factor(s) involved in the incidence of abnormal lipid metabolism upon lipopolysaccharide injection and hepatoma transplantation.     

Effect of serum lipoproteins on stereoselective halofantrine metabolism by rat hepatocytes

Experimental hyperlipidemia has shown to decrease cytochrome P450 3A4 and 2C11 expression and to increase liver concentrations and the plasma protein binding of halofantrine (HF) enantiomers. The present study examined the effect of hyperlipidemic (HL) serum on the metabolism of HF enantiomers by primary rat hepatocytes. Hepatocytes from normolipidemic (NL) and HL (poloxamer 407 treated) rats were incubated with rac-HF in cell media with or without additional rat serum (5%). In those incubations with rat serum, the hepatocytes were preincubated or coincubated with serum from NL or HL rats. Rat serum-free hepatocyte incubations served as controls. Stereospecific assays were used to measure HF and desbutylhalofantrine (its major metabolite) enantiomer concentrations in whole well contents (cells + media). Concentrations of desbutylhalofantrine were not measurable. The disappearance (apparent metabolism) of (-)-HF exceeded that of antipode, but HF metabolism did not differ between hepatocytes from NL and HL rats. Coincubation of HL rat serum with NL hepatocytes caused a significant decrease in the disappearance of (-)-HF, whereas in HL hepatocytes, a substantially decreased apparent metabolism was noted for both enantiomers. Compared with NL serum, (-)-HF disappearance was significantly lowered upon preincubation of NL hepatocytes with HL serum. A combination of factors including diminished drug metabolizing or lipoprotein receptor expression, and increased plasma protein binding in the wells, may have contributed to a decrease in apparent metabolism of the HF enantiomers in the presence of lipoproteins from HL rat serum.     

中老年男性患者血脂代谢特点及与年龄等因素的相关分析

目的:探讨中老年男性患者血脂代谢特点及与年龄等因素的相关性。方法:资料来自2006年6月于我院干部门诊进行健康查体的1603例中老年男性患者(排除正在服用降脂药物的患者),采用全自动生化分析仪对血清总胆固醇(TC)、血清甘油三酯(TG)、血清低密度脂蛋白胆固醇(LDL-c)、血清高密度脂蛋白胆固醇(HDL-c)、空腹血糖(FBG)、血肌酐(Cr)及血尿酸(UA)等指标进行测定,同时记录身高、体重及血压等基本资料。结果:入选患者血脂异常总检出率为56.27%,其中TC、TG、HDL-c及LDL-c异常检出率分别为36.74%、28.20%、10.79%及6.92%,以TC、TG异常为主。与50~59岁组相比,80岁以上高龄老年组TG异常及HDL-c异常检出率显著降低,TC及TG水平显著降低,HDL-c水平显著升高(P<0.05)。在校正BMI、SBP、DBP、UA、FBG及CCr等危险因素影响后的多元线性回归分析发现,年龄每升高10岁,TC、TG分别降低约0.097 mmol/L及0.087 mmol/L,HDL-c升高约0.113 mmol/L。结论:中老年男性患者血脂异常以高TC和高TG为主,TC、TG与年龄呈负相关,HDL-c与年龄呈正相关,需针对高龄老年患者血脂代谢特点进行合理调脂治疗。     

Chronopharmacology of simvastatin on hyperlipidaemia in high‐fat diet‐fed obese mice

The chronopharmacology refers to the utilization of physiological circadian rhythms to optimize the administration time of drugs, thus increasing their efficacy and safety, or reducing adverse effects. Simvastatin is one of the most widely prescribed drugs for the treatment of hypercholesterolaemia, hyperlipidemia and coronary artery disease. There are conflicting statements regarding the timing of simvastatin administration, and convincing experimental evidence remains unavailable. Thus, we aimed to examine whether different administration times would influence the efficacy of simvastatin. High‐fat diet‐fed mice were treated with simvastatin at zeitgeber time 1 (ZT1) or ZT13, respectively, for nine weeks. Simvastatin showed robust anti‐hypercholesterolaemia and anti‐hyperlipidemia effects on these obese mice, regardless of administration time. However, simvastatin administrated at ZT13, compared to ZT1, was more functional for decreasing serum levels of total cholesterol, triglycerides, non‐esterified free fatty acids and LDL cholesterol, as well as improving liver pathological characteristics. In terms of possible mechanisms, we found that simvastatin did not alter the expression of hepatic circadian clock gene in vivo, although it failed to change the period, phase and amplitude of oscillation patterns in Per2::Luc U2OS and Bmal1::Luc U2OS cells in vitro. In contrast, simvastatin regulated the expression of Hmgcr, Mdr1 and Slco2b1 in a circadian manner, which potentially contributed to the chronopharmacological function of the drug. Taken together, we provide solid evidence to suggest that different administration times affect the lipid‐lowering effects of simvastatin.     

Transgenic mice express human MPO -463G/A alleles at atherosclerotic lesions, developing hyperlipidemia and obesity in -463G males

Myeloperoxidase (MPO) is an oxidant-generating enzyme present in macrophages at atherosclerotic lesions and implicated in coronary artery disease (CAD). Although mouse models are important for investigating the role of MPO in atherosclerosis, neither mouse MPO nor its oxidation products are detected in lesions in murine models. To circumvent this problem, we generated transgenic mice expressing two functionally different human MPO alleles, with either G or A at position -463, and crossed these to the LDL receptor-deficient (LDLR(-/-)) mouse. The -463G allele is linked to higher MPO expression and increased CAD incidence in humans. Both MPO alleles were expressed in a subset of lesions in high-fat-fed LDLR(-/-) mice, notably at necrotic lesions with cholesterol clefts. MPOG-expressing LDLR(-/-) males (but not females) developed significantly higher serum cholesterol, triglycerides, and glucose, all correlating with increased weight gain/obesity, implicating MPO in lipid homeostasis. The MPOG- and MPOA-expressing LDLR(-/-) males also exhibited significantly larger aortic lesions than control LDLR(-/-) males. The human MPO transgenic model will facilitate studies of MPO involvement in atherosclerosis and lipid homeostasis.     

microRNA-181a represses ox-LDL-stimulated inflammatory response in dendritic cell by targeting c-Fos

Oxidized LDL (ox-LDL) activates dendritic cells (DCs), thereby initiating inflammation responses in atherosclerosis, yet the modulatory mechanisms remain unclear. MicroRNAs (miRNAs) are important regulators for DC functions. This study evaluated the regulation by miRNAs of the ox-LDL-induced DC immune response. In CD11c⁺ DCs from ApoE-deficient mice with hyperlipidemia, microRNA miR-181a was significantly up-regulated. In cultured bone marrow-derived DCs (BMDCs), ox-LDL promoted DC maturation and up-regulated miR-181a expression. Abundance of miR-181a attenuated ox-LDL-induced CD83 and CD40 expression, inhibited the secretion of interleukin (IL)-6 and TNF-α, and up-regulated IL-10, an important anti-inflammatory cytokine that was inhibited by ox-LDL. Inhibition of the endogenous miR-181a reversed the effects on CD83 and CD40 as well as the effects on IL-6 and TNF-α. The putative target genes of miR-181a were evaluated by gene ontology assessment, and the c-Fos-mediated inflammation pathway was identified. miR-181a targeted the 3′ untranslated region of c-Fos mRNA by luciferase experiments. Thus, abundance of miR-181a reduced c-Fos protein, whereas inhibition of miR-181a increased c-Fos protein in BMDCs. We therefore suggest that miR-181a attenuates ox-LDL-stimulated immune inflammation responses by targeting c-Fos in DCs.