Angiopeptin Inhibition of Myointimal Hyperplasia after Balloon Angioplasty of Large Arteries in Hypercholesterolaemic Rabbits

1. Currently, a wide range of drugs is being evaluated for the ability to prevent the restenosis which frequently accompanies percutaneous transluminal coronary angioplasty. Patients undergoing angioplasty are generally hypercholesterolaemic and therefore the possibility that plasma lipids may compromise the efficacy of anti-restenotic drugs must be assessed. A promising drug in several clinical trials for the prevention of restenosis is angiopeptin, an octapeptide analogue of somatostatin that possesses a highly lipophilic terminal. 2. The effect of angiopeptin on myointimal hyperplasia was studied in a rabbit model of arterial balloon catheter injury where the rabbits were made hypercholesterolaemic by a 0.5% cholesterol diet. The degree of subsequent myointimal thickening was measured by morphometry. 3. Angiopeptin (20 μg day−1 kg−1) significantly inhibited myointimal thickening by an average of 47% in the infrarenal aorta and both the common and external iliac arteries in the presence of elevated plasma lipids concentrations. Low dose angiopeptin (2 μg day−1 kg−1) significantly inhibited myointimal thickening in the external iliac artery but not in the other two vessels. 4. Angiopeptin treatment (20 μg day−1 kg−1) did not significantly modify the plasma cholesterol, very-low-density lipoprotein, intermediate-sized low-density lipoprotein, low-density lipoprotein and high-density lipoprotein concentrations that were elevated by the 0.5% cholesterol diet. 5. We conclude that the inhibitory effect of angiopeptin is largely unaffected by elevated plasma lipid concentrations and that this drug did not modify plasma lipid concentrations in rabbits.

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(Pro)renin Receptor Inhibition Reduces Plasma Cholesterol and Triglycerides but Does Not Attenuate Atherosclerosis in Atherosclerotic Mice

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.725203 ◽

2021 ◽

Vol 8 ◽

Author(s):

Dien Ye ◽

Xiaofei Yang ◽

Liwei Ren ◽

Hong S. Lu ◽

Yuan Sun ◽

...

Keyword(s):

Plasma Lipids ◽

Inflammatory Responses ◽

Plasma Cholesterol ◽

Low Density Lipoprotein ◽

Plasma Lipid ◽

Density Lipoprotein ◽

Low Density ◽

Beneficial Effects ◽

Receptor Inhibition ◽

Density Lipoprotein Receptor

Objective: Elevated plasma cholesterol concentrations contributes to ischemic cardiovascular diseases. Recently, we showed that inhibiting hepatic (pro)renin receptor [(P)RR] attenuated diet-induced hypercholesterolemia and hypertriglyceridemia in low-density lipoprotein receptor (LDLR) deficient mice. The purpose of this study was to determine whether inhibiting hepatic (P)RR could attenuate atherosclerosis.Approach and Results: Eight-week-old male LDLR−/− mice were injected with either saline or N-acetylgalactosamine-modified antisense oligonucleotides (G-ASOs) primarily targeting hepatic (P)RR and were fed a western-type diet (WTD) for 16 weeks. (P)RR G-ASOs markedly reduced plasma cholesterol concentrations from 2,211 ± 146 to 1,128 ± 121 mg/dL. Fast protein liquid chromatography (FPLC) analyses revealed that cholesterol in very low-density lipoprotein (VLDL) and intermediate density lipoprotein (IDL)/LDL fraction were potently reduced by (P)RR G-ASOs. Moreover, (P)RR G-ASOs reduced plasma triglyceride concentrations by more than 80%. Strikingly, despite marked reduction in plasma lipid concentrations, atherosclerosis was not reduced but rather increased in these mice. Further testing in ApoE−/− mice confirmed that (P)RR G-ASOs reduced plasma lipid concentrations but not atherosclerosis. Transcriptomic analysis of the aortas revealed that (P)RR G-ASOs induced the expression of the genes involved in immune responses and inflammation. Further investigation revealed that (P)RR G-ASOs also inhibited (P)RR in macrophages and in enhanced inflammatory responses to exogenous stimuli. Moreover, deleting the (P)RR in macrophages resulted in accelerated atherosclerosis in WTD fed ApoE−/− mice.Conclusion: (P)RR G-ASOs reduced the plasma lipids in atherosclerotic mice due to hepatic (P)RR deficiency. However, augmented pro-inflammatory responses in macrophages due to (P)RR downregulation counteracted the beneficial effects of lowered plasma lipid concentrations on atherosclerosis. Our study demonstrated that hepatic (P)RR and macrophage (P)RR played a counteracting role in atherosclerosis.

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Plasma Lipid and Lipoprotein Abnormalities in Patients with Malabsorption

Clinical Science ◽

10.1042/cs0450583 ◽

1973 ◽

Vol 45 (5) ◽

pp. 583-592 ◽

Cited By ~ 2

Author(s):

Gilbert R. Thompson ◽

J. Paul Miller

Keyword(s):

Plasma Lipids ◽

Plasma Cholesterol ◽

Low Density Lipoprotein ◽

Plasma Lipid ◽

Density Lipoprotein ◽

Serum Triglyceride ◽

Plasma Lipoproteins ◽

Low Density ◽

Cholesterol Levels ◽

Lipids And Lipoproteins

1. Plasma lipids and lipoproteins have been studied in control subjects and patients with various types of steatorrhoea. 2. Low plasma cholesterol levels were found in malabsorbers and were associated with decreased amounts of low-density lipoprotein (LDL) in males and high-density lipoprotein (HDL) in females. 3. Serum triglyceride levels were normal in males, but exceeded control values in some of the females, due to an increase in very-low-density lipoprotein. 4. LDL composition was abnormal in both male and female malabsorbers, with a decreased proportion of cholesterol ester and an increased proportion of triglyceride. There was also an increased proportion of triglyceride in HDL. 5. These findings show that malabsorption markedly influences not only the concentration but also the composition of plasma lipoproteins.

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Plasma lipids, lipoproteins, and triglyceride turnover in eu- and hypo-thyroid rats and rats on a hypocaloric diet

Canadian Journal of Biochemistry ◽

10.1139/o81-099 ◽

1981 ◽

Vol 59 (8) ◽

pp. 715-721 ◽

Cited By ~ 6

Author(s):

Ladislav Dory ◽

Brian R. Krause ◽

Paul S. Roheim

Keyword(s):

Half Life ◽

Plasma Lipids ◽

Plasma Cholesterol ◽

Low Density Lipoprotein ◽

Caloric Intake ◽

Plasma Lipid ◽

Density Lipoprotein ◽

Plasma Triglyceride ◽

Low Density ◽

Control Groups

Lipid and lipoprotein concentration, and triglyceride turnover were studied in control, thyroidectomized, and pair-fed control rats (pair-fed to match the food intake of the thyroidectomized rats). Thyroidectomy induced a significant increase in plasma cholesterol (and low density lipoprotein) concentrations and a decrease in plasma triglyceride (and very low density lipoprotein) concentrations. Changes in similar direction but of smaller magnitude were observed in the plasma of the pair-fed control rats. To further investigate triglyceride metabolism in these three groups of animals, triglyceride turnover was studied in fasted, unrestrained, and unanesthetized rats, following injection of [2-3H]glycerol. Peak incorporation of [2-3H]glycerol into plasma triglyceride occurred in all three groups of animals at 25 min after precursor administration, although the maximal incorporation was substantially lower in the thyroidectomized group than in either of the control groups. Thereafter, plasma triglyceride radioactivity decayed monoexponentially with a half-life of 24 ± 1 min for both normal and pair-fed control rats, compared with the half-life of 41 ± 3 min observed in the thyroidectomized rats. The calculated apparent fractional catabolic rates were thus 0.029 min−1 for both control groups and only 0.017 min−1 for the thyroidectomized animals. The apparent total catabolic rates of plasma triglyceride were 299 ± 11, 138 ± 11, and 48 ± 4 μg triglyceride∙min−1 for the normal controls, pair-fed controls, and thyroidectomized rats, respectively. These data further emphasize the importance of thyroid hormones in regulating plasma lipid and lipoprotein metabolism and, specifically, indicate that hypothyroidism results in a reduction of triglyceride secretion into, and the removal from, circulation. Furthermore, evidence was presented that the decreased caloric intake of the hypothyroid animals cannot, in itself, account for this observation.

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Dihomo-γ-Linolenic Acid in Patients with Atherosclerosis: Effects on Platelet Aggregation, Plasma Lipids and Low-Density Lipoprotein-Induced Inhibition of Prostacyclin Generation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661054 ◽

1984 ◽

Vol 51 (02) ◽

pp. 186-188 ◽

Cited By ~ 11

Author(s):

A Szczeklik ◽

R J Gryglewski ◽

K Sladek ◽

E Kostka-Trąbka ◽

A Żmuda

Keyword(s):

Linolenic Acid ◽

Plasma Lipids ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Thromboxane A2 ◽

Low Density ◽

Red Cell ◽

Double Blind ◽

Daily Dose ◽

Antithrombotic Effects

SummaryDihomo-γ-linolenic acid (DHLA), a precursor of monoenoic anti-aggregatory prostaglandins (PGE1, PGD2), was administered for 4 weeks in a daily dose of 1.0 g into 33 patients with atherosclerosis on a basis of a double-blind trial. Comparison of treatment and placebo groups revealed elevation of DHLA in red cell lipids in DHLA-treated subjects. No differences, however, between the two groups could be observed in platelet aggregability, thromboxane A2 generation by platelets, serum cholesterol, PGE1 and PGE2 levels, and in inhibitory activity of low-density lipoproteins against prostacyclin synthetizing system in arteries. The dietary supplementation used did not lead to distinct antithrombotic effects.

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Dihomo-γ-Linolenic Acid in Patients with Atherosclerosis: Effects on Platelet Aggregation, Plasma Lipids and Low-Density Lipoprotein-Induced Inhibition of Prostacyclin Generation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1660163 ◽

1985 ◽

Vol 54 (04) ◽

pp. 901-901

Author(s):

D P Mikhailidis ◽

M A Barradas ◽

P Dandona

Keyword(s):

Platelet Aggregation ◽

Linolenic Acid ◽

Plasma Lipids ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Low Density

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Long-term fasting improves lipoprotein-associated atherogenic risk in humans

European Journal of Nutrition ◽

10.1007/s00394-021-02578-0 ◽

2021 ◽

Author(s):

Franziska Grundler ◽

Dietmar Plonné ◽

Robin Mesnage ◽

Diethard Müller ◽

Cesare R. Sirtori ◽

...

Keyword(s):

Low Density Lipoprotein ◽

Plasma Lipid ◽

Density Lipoprotein ◽

Apolipoprotein A1 ◽

Health Concern ◽

Low Density ◽

Lipoprotein Subclasses ◽

Ldl Particles ◽

Increased Risk

Abstract Purpose Dyslipidemia is a major health concern associated with an increased risk of cardiovascular mortality. Long-term fasting (LF) has been shown to improve plasma lipid profile. We performed an in-depth investigation of lipoprotein composition. Methods This observational study included 40 volunteers (50% men, aged 32–65 years), who underwent a medically supervised fast of 14 days (250 kcal/day). Changes in lipid and lipoprotein levels, as well as in lipoprotein subclasses and particles, were measured by ultracentrifugation and nuclear magnetic resonance (NMR) at baseline, and after 7 and 14 fasting days. Results The largest changes were found after 14 fasting days. There were significant reductions in triglycerides (TG, − 0.35 ± 0.1 mmol/L), very low-density lipoprotein (VLDL)-TG (− 0.46 ± 0.08 mmol/L), VLDL-cholesterol (VLDL-C, − 0.16 ± 0.03 mmol/L) and low-density lipoprotein (LDL)-C (− 0.72 ± 0.14 mmol/L). Analysis of LDL subclasses showed a significant decrease in LDL1-C (− 0.16 ± 0.05 mmol/L), LDL2-C (− 0.30 ± 0.06 mmol/L) and LDL3-C (− 0.27 ± 0.05 mmol/L). NMR spectroscopy showed a significant reduction in large VLDL particles (− 5.18 ± 1.26 nmol/L), as well as large (− 244.13 ± 39.45 nmol/L) and small LDL particles (− 38.45 ± 44.04 nmol/L). A significant decrease in high-density lipoprotein (HDL)-C (− 0.16 ± 0.04 mmol/L) was observed. By contrast, the concentration in large HDL particles was significantly raised. Apolipoprotein A1 decreased significantly whereas apolipoprotein B, lipoprotein(a), fibrinogen and high-sensitivity C-reactive protein were unchanged. Conclusion Our results suggest that LF improves lipoprotein levels and lipoprotein subclasses and ameliorates the lipoprotein-associated atherogenic risk profile, suggesting a reduction in the cardiovascular risk linked to dyslipidemia. Trial Registration Study registration number: DRKS-ID: DRKS00010111 Date of registration: 03/06/2016 “retrospectively registered”.

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Emodin alleviated hyperlipidemia and hepatic lipid metabolism in zebrafish larvae fed a high-cholesterol diet via AMPK/SREBP-2/PCSK9/LDLR signaling pathway

10.21203/rs.3.rs-796126/v1 ◽

2021 ◽

Author(s):

Linfeng He ◽

Cheng Wang ◽

Yafang Zhang ◽

Chaocheng Guo ◽

Yan Wan ◽

...

Keyword(s):

Lipid Metabolism ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

High Cholesterol Diet ◽

Low Density ◽

Cholesterol Diet ◽

High Cholesterol ◽

Cholesterol Accumulation ◽

Hepatic Lipid ◽

Zebrafish Larvae

Abstract BackgroundEmodin (EM) is one of bioactive components extracted from Rheum palmatum L. (Dahuang), which possesses numerous pharmacological activities including hypolipidemic effect. However, the potential action of EM on hyperlipidemia (HLP) remains unclear. Here, the theraputic effect of EM against HLP were investigated.MethodsIn this study, the hypolipidemic properties of EM were evaluated using high-cholesterol diet (HCD)-stimulated zebrafish larvae model. The body weight, body length and body mass index (BMI) was measured. The total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) as well as the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected by corresponding assay kits. Tg (flil: eGFP) zebrafish were utilized to observe vascular cholesterol accumulation and Tg (mpx: eGFP) zebrafish to visualize and quantify neutrophil inflammation. The hepatic lipid deposition and hepatic histopathology were analyzed by Oil red O staining and H&E staining, respectively. Finally, the underlying mechanism of EM were investigated using real-time quantitative PCR (RT-qPCR) analysis to assess the gene levels of adenosine monophosphate-activated protein kinase alpha (AMPKα), sterol regulatory element binding protein 2 (SREBP-2), proprotein convertase subtilisin kexin 9 (PCSK9), low-density lipoprotein receptor (LDLR), 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), adenosine triphosphate binding cassette transporter A1 (ABCA1) and adenosine triphosphate binding cassette transporter G1 (ABCG1).ResultsOur data indicated that EM reduced obesity of zebrafish as evidenced by the decrease in body weight, body length and BMI. EM significantly reduced TC, TG, and LDL-C, and increased HDL-C contents. Moreover, it displayed a prominent inhibitory effect on blood cholesterol accumulation, hepatic lipid accumulation, and neutrophil inflammation in vascular site. Additionally, EM improved the liver function through decreasing ALT and AST levels of zebrafish with HCD-induced hepatosteatosis. Further investigation showed that EM treatment attenuated lipid accumulation via upregulating the expression of AMPKα, LDLR, ABCA1 and ABCG1, and downregulating the expression of SREBP-2, PCSK9 and HMGCR.ConclusionTo conclude, EM alleviated lipid metabolism disorder symptoms caused by HCD via modulating AMPK/SREBP-2/PCSK9/LDLR pathway in larvae, suggesting that EM may be developed into hypolipidmic agent for treating lipid metabolism related diseases.

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Modulation of hepatic apolipoprotein B, 3-hydroxy-3-methylglutaryl-CoA reductase and low-density lipoprotein receptor mRNA and plasma lipoprotein concentrations by defined dietary fats. Comparison of trimyristin, tripalmitin, tristearin and triolein

Biochemical Journal ◽

10.1042/bj3110167 ◽

1995 ◽

Vol 311 (1) ◽

pp. 167-173 ◽

Cited By ~ 31

Author(s):

A J Bennett ◽

M A Billett ◽

A M Salter ◽

E H Mangiapane ◽

J S Bruce ◽

...

Keyword(s):

Fatty Acids ◽

Plasma Lipids ◽

Low Density Lipoprotein ◽

Lipoprotein Metabolism ◽

Density Lipoprotein ◽

Dietary Fats ◽

Low Density ◽

Mrna Levels ◽

Expression Of Genes ◽

Coa Reductase

Different dietary fatty acids exert specific effects on plasma lipids but the mechanism by which this occurs is unknown. Hamsters were fed on low-cholesterol diets containing triacylglycerols enriched in specific saturated fatty acids, and effects on plasma lipids and the expression of genes involved in hepatic lipoprotein metabolism were measured. Trimyristin and tripalmitin caused significant rises in low-density lipoprotein (LDL) cholesterol which were accompanied by significant reductions in hepatic LDL receptor mRNA levels. Tripalmitin also increased hepatic expression of the apolipoprotein B gene, implying an increased production of LDL via very-low-density lipoprotein (VLDL) and decreased removal of LDL in animals fed this fat. Hepatic levels of 3-hydroxy-3-methylglutaryl-CoA reductase mRNA did not vary significantly between the groups. Compared with triolein, tristearin had little effect on hepatic gene expression or total plasma cholesterol. However, it caused a marked decrease in VLDL cholesterol and a rise in LDL cholesterol such that overall it appeared to be neutral. Lipid analysis suggested a rapid desaturation of much of the dietary stearate. The differential changes in plasma lipids and hepatic mRNA levels induced by specific dietary fats suggests a role for fatty acids or a metabolite thereof in the regulation of the expression of genes involved in lipoprotein metabolism.

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