Dietary Indigenous Cinnamon (Cinnamomum osmophloeum) Leaf Powder Reduces Plasma Lipid in Hypercholesterolemia Hamsters

Indigenous cinnamon ( Cinnamomum osmophloeum Kaneh) is a native tree species in Taiwan and has been reported to have various bioactivities including insecticidal, larvicidal, and antimicrobial effects. The chemical finger print of C. osmophloeum is similar to that of commercial cinnamon species with lower coumarin content. The present study was aimed to investigate the antidyslipidemia effects of indigenous cinnamon ( Cinnamomum osmophloeum Kaneh) leaf powder (CoLP) on hypercholesterolemia hamsters. Hyperlipidemia was induced by high-cholesterol (HChol) diet for 4 weeks. Two percent and 5% CoLP, and gemfibrozil (positive control; 0.25%) were administered for 10 weeks following HChol diet. Control groups were fed with normal diet (ND) or ND+5% CoLP. Behavioral, physiological, and serum biochemical parameters were determined. We found that oral administration of CoLP for 10 weeks significantly reduced the HChol-induced increase of total cholesterol (TC), triglyceride, and low-density lipoprotein levels in plasma of hamsters. In addition, HChol-induced elevation of serum glutamic oxaloacetic transaminase and glutamic pyruvic transaminase levels was significantly reversed by CoLP in a dose-dependent manner, whereas blood urea nitrogen and creatinine levels were unaffected. Further standard diagnostic tests support that consumption of CoLP did not show any behavioral and morphological changes in hamsters. Furthermore, chemical composition analysis revealed that two new flavanol glycosides, kaempferol-3- O-α-l-rhamnopyranosyl-(1→2)-α-l-arabinofuranosyl-7- O-α-l-rhamnopyranoside (4) and kaempferol-3- O-β -d-apiofuranosyl-(1→2)-α-l-arabinofuranoside (5) along with 4 known flavonoid glycosides were identified in leaves of C. osmophloeum. Taken together, these results concluded that CoLP possessed strong antidyslipidemic effects. Therefore, C. osmophloeum leaves could be a safe food supplement for treating hypercholesterolemia.

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The effect of daily baked bean (Phaseolus vulgaris) consumption on the plasma lipid levels of young, normo-cholesterolaemic men

British Journal Of Nutrition ◽

10.1079/bjn19890114 ◽

1989 ◽

Vol 61 (2) ◽

pp. 257-265 ◽

Cited By ~ 42

Author(s):

Susan M. Shutler ◽

Gemma M. Bircher ◽

Jacki A. Tredger ◽

Linda M. Morgan ◽

Ann F. Walker ◽

...

Keyword(s):

Phaseolus Vulgaris ◽

Plasma Cholesterol ◽

Plasma Lipid ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Normal Diet ◽

Male Students ◽

C Peptide ◽

Tomato Sauce ◽

Cholesterol Ratio

1. Thirteen normo-cholesterolaemic male students consumed one 450 g can of baked beans (Phaseolus vulgaris) in tomato sauce, daily, for 14 d as part of their normal diet. After a 14 d washout period, eleven of the students went on to consume one 440 g can of spaghetti in tomato sauce, daily, for 14 d.2. Fasting blood samples were taken frequently for measurement of plasma cholesterol, high-density lipoprotein (HDL)-cholesterol, triacylglycerols, glucose, insulin and C-peptide. Diet diaries (3 d) were completed by the subjects during each period.3. Consumption of beans and spaghetti led to a significant reduction in the amount of fat eaten daily (P< 0.05). Bean consumption also resulted in significant increases in protein, fibre and sugar intakes (P< 0.02,P< 0.001 andP< 0.05 respectively).4. During the bean-eating period the mean total plasma cholesterol level of the students fell significantly from 5.1 to 4.5 mmol/l (P< 0.02). No reduction in plasma cholesterol occurred during the spaghetti-eating period.5. HDL-cholesterol levels fell significantly during both periods (P< 0.001), but HDL:total cholesterol ratio was significantly reduced only during the spaghetti-eating period (P< 0.001). Neither beans nor spaghetti affected triacylglycerol, insulin or C-peptide levels.6. The benefits of a legume-rich diet are discussed.

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Circulating Rather Than Intestinal PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Regulates Postprandial Lipemia in Mice

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314194 ◽

2020 ◽

Vol 40 (9) ◽

pp. 2084-2094 ◽

Cited By ~ 1

Author(s):

Damien Garçon ◽

François Moreau ◽

Audrey Ayer ◽

Wieneke Dijk ◽

Xavier Prieur ◽

...

Keyword(s):

Diabetes Mellitus ◽

Monoclonal Antibody ◽

Low Density Lipoprotein ◽

Postprandial Lipemia ◽

Plasma Lipid ◽

Density Lipoprotein ◽

Dependent Manner ◽

Proprotein Convertase ◽

Pcsk9 Inhibitors ◽

Relative Contribution

Objective: Increased postprandial lipemia (PPL) is an independent risk factor for atherosclerotic cardiovascular diseases. PCSK9 (Proprotein convertase subtilisin kexin type 9) is an endogenous inhibitor of the LDLR (low-density lipoprotein receptor) pathway. We previously showed that PCSK9 inhibition in mice reduces PPL. However, the relative contribution of intracellular intestinal PCSK9 or liver-derived circulating PCSK9 to this effect is still unclear. Approach and Results: To address this issue, we generated the first intestine-specific Pcsk9 -deficient (i- Pcsk9 −/− ) mouse model. PPL was measured in i- Pcsk9 −/− as well as in wild-type and streptozotocin-induced diabetic mice following treatment with a PCSK9 monoclonal antibody (alirocumab). Blocking the circulating form of PCSK9 with alirocumab significantly reduced PPL, while overexpressing human PCSK9 in the liver of full Pcsk9 −/− mice had the opposite effect. Alirocumab regulated PPL in a LDLR-dependent manner as this effect was abolished in Ldlr −/− mice. In contrast, i- Pcsk9 −/− mice did not exhibit alterations in plasma lipid parameters nor in PPL. Finally, PPL was highly exacerbated by streptozotocin-induced diabetes mellitus in Pcsk9 +/+ but not in Pcsk9 −/− mice, an effect that was mimicked by the use of alirocumab in streptozotocin-treated Pcsk9 +/+ mice. Conclusions: Taken together, our data demonstrate that PPL is significantly altered by full but not intestinal PCSK9 deficiency. Treatment with a PCSK9 monoclonal antibody mimics the effect of PCSK9 deficiency on PPL suggesting that circulating PCSK9 rather than intestinal PCSK9 is a critical regulator of PPL. These data validate the clinical relevance of PCSK9 inhibitors to reduce PPL, especially in patients with type 2 diabetes mellitus.

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Cardioprotective Effects of Diet with Different Grains on Lipid Profiles and Antioxidative System in Obesity-Induced Rats

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000097 ◽

2012 ◽

Vol 82 (2) ◽

pp. 85-93 ◽

Cited By ~ 9

Author(s):

Y. Kim ◽

H. Shin ◽

S. Lee

Keyword(s):

Aortic Wall ◽

Plasma Lipids ◽

Antioxidant Activities ◽

Plasma Lipid ◽

Density Lipoprotein ◽

Thiobarbituric Acid ◽

Lipid Profiles ◽

Dietary Lipids ◽

Male Rats

In the present study, the nutritional quality of four grains including adlay (AD), buckwheat (BW), glutinous barley (GB), and white rice (WR) were evaluated in terms of plasma lipid parameters, gut transit time, and thickness of the aortic wall in rats. The rats were then raised for 4 weeks on the high-fat diet based on the American Institute of Nutrition-93 (AIN-93 G) diets containing 1 % cholesterol and 20 % dietary lipids. Forty male rats were divided into 4 groups and raised for 4 weeks with a diet containing one of the following grains: WR, AD, BW, or WB. The level of thiobarbituric acid-reactive substances (TBARS) in liver was shown to be higher in rats by the order of those fed WR, AD, GB, and BW. This indicates that other grains decreased oxidative stress in vivo more than WR. The superoxide dismutase, glutathione, glutathione peroxidase, and glutathione reductase levels in the AD, BW, and GB groups were significantly higher than those in the WR group (p < 0.05). Plasma lipid profiles differed significantly according to grain combination, and decreased aortic wall thickness was consistent with the finding of decreased plasma low-density lipoprotein cholesterol (LDL-C) (p < 0.05) and increased high-density lipoprotein (HDL-C) in rats fed AD, BW, and GB (p < 0.001). The antioxidant and hypolipidemic capacities of grains are quite high, especially those of adlay, buckwheat, and glutinous barley. In conclusion, this study has demonstrated that the whole grains had a cardioprotective effect. This effect was related to several mechanisms that corresponded to lowering plasma lipids, decreasing TBARS, and increasing antioxidant activities.

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The Modulation of PCSK9 and LDLR by Supercritical CO2 Extracts of Mentha longifolia and Isolated Piperitone Oxide, an In Vitro Study

Molecules ◽

10.3390/molecules26133886 ◽

2021 ◽

Vol 26 (13) ◽

pp. 3886

Author(s):

Stefania Sut ◽

Irene Ferrarese ◽

Maria Giovanna Lupo ◽

Nicola De Zordi ◽

Elisa Tripicchio ◽

...

Keyword(s):

Mass Spectrometry ◽

Cell Lines ◽

Hepatoma Cell ◽

Density Lipoprotein ◽

In Vitro Study ◽

Volatile Constituent ◽

Dependent Manner ◽

Human Hepatoma Cell ◽

Concentration Dependent Manner

In the present study the ability of supercritical carbon dioxide (SCO2) extracts of M. longifolia L. leaves to modulate low-density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) expression was evaluated in cultured human hepatoma cell lines Huh7 and HepG2. Two SCO2 extracts, one oil (ML-SCO2) and a semisolid (MW-SCO2), were subjected to detailed chemical characterization by mono- and bidimensional nuclear magnetic resonance (1D, 2D-NMR), gas chromatography coupled with mass spectrometry (GC-MS) and liquid chromatography coupled with mass spectrometry (LC-MS). Chemical analysis revealed significant amounts of fatty acids, phytosterols and terpenoids. ML-SCO2 was able to induce LDLR expression at a dose of 60 µg/mL in HuH7 and HepG2 cell lines. Furthermore, ML-SCO2 reduced PCSK9 secretion in a concentration-dependent manner in both cell lines. Piperitone oxide, the most abundant compound of the volatile constituent of ML-SCO2 (27% w/w), was isolated and tested for the same targets, showing a very effective reduction of PCSK9 expression. The overall results revealed the opportunity to obtain a new nutraceutical ingredient with a high amount of phytosterols and terpenoids using the SCO2 extraction of M. longifolia L., a very well-known botanical species used as food. Furthermore, for the first time we report the high activity of piperitone oxide in the reduction of PCSK9 expression.

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Improvement of Obesity and Dyslipidemic Activity of Amomum tsao-ko in C57BL/6 Mice Fed a High-Carbohydrate Diet

Molecules ◽

10.3390/molecules26061638 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1638

Author(s):

Ju-Hyoung Park ◽

Eun-Kyung Ahn ◽

Min Hee Hwang ◽

Young Jin Park ◽

Young-Rak Cho ◽

...

Keyword(s):

Body Weight Gain ◽

Subcutaneous Fat ◽

Density Lipoprotein ◽

Ethanol Extract ◽

Cardiac Risk ◽

Normal Diet ◽

High Carbohydrate Diet ◽

Atherogenic Index ◽

Carbohydrate Diet ◽

High Carbohydrate

Amomum tsao-ko Crevost et Lemaire (Zingiberaceae) is a medicinal herb found in Southeast Asia that is used for the treatment of malaria, abdominal pain, dyspepsia, etc. The aim of this study was to investigate the effect of an ethanol extract of Amomum tsao-ko (EAT) on obesity and hyperlipidemia in C57BL/6 mice fed a high-carbohydrate diet (HCD). First, the mice were divided into five groups (n = 6/group) as follows: normal diet, HCD, and HCD+EAT (100, 200, and 400 mg/kg/day), which were orally administered with EAT daily for 84 days. Using microcomputed tomography (micro-CT) analysis, we found that EAT inhibited not only body-weight gain, but also visceral fat and subcutaneous fat accumulation. Histological analysis confirmed that EAT decreased the size of fat tissues. EAT consistently improved various indices, including plasma levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein, high-density lipoprotein, atherogenic index, and cardiac risk factors, which are related to dyslipidemia—a major risk factor for heart disease. The contents of TC and TG, as well as the lipid droplets of HCD-induced hepatic accumulation in the liver tissue, were suppressed by EAT. Taken together, these findings suggest the possibility of developing EAT as a therapeutic agent for improving HCD-induced obesity and hyperlipidemia.

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Low-density lipoprotein receptor-related protein 1 (LRP1) is a novel receptor for apolipoprotein A4 (APOA4) in adipose tissue

Scientific Reports ◽

10.1038/s41598-021-92711-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jie Qu ◽

Sarah Fourman ◽

Maureen Fitzgerald ◽

Min Liu ◽

Supna Nair ◽

...

Keyword(s):

Adipose Tissue ◽

Glucose Uptake ◽

Molecular Mechanisms ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Receptor ◽

Dependent Manner ◽

Related Protein ◽

Density Lipoprotein Receptor ◽

Lipoprotein Receptor Related Protein

AbstractApolipoprotein A4 (APOA4) is one of the most abundant and versatile apolipoproteins facilitating lipid transport and metabolism. APOA4 is synthesized in the small intestine, packaged onto chylomicrons, secreted into intestinal lymph and transported via circulation to several tissues, including adipose. Since its discovery nearly 4 decades ago, to date, only platelet integrin αIIbβ3 has been identified as APOA4 receptor in the plasma. Using co-immunoprecipitation coupled with mass spectrometry, we probed the APOA4 interactome in mouse gonadal fat tissue, where ApoA4 gene is not transcribed but APOA4 protein is abundant. We demonstrate that lipoprotein receptor-related protein 1 (LRP1) is the cognate receptor for APOA4 in adipose tissue. LRP1 colocalized with APOA4 in adipocytes; it interacted with APOA4 under fasting condition and their interaction was enhanced during lipid feeding concomitant with increased APOA4 levels in plasma. In 3T3-L1 mature adipocytes, APOA4 promoted glucose uptake both in absence and presence of insulin in a dose-dependent manner. Knockdown of LRP1 abrogated APOA4-induced glucose uptake as well as activation of phosphatidylinositol 3 kinase (PI3K)-mediated protein kinase B (AKT). Taken together, we identified LRP1 as a novel receptor for APOA4 in promoting glucose uptake. Considering both APOA4 and LRP1 are multifunctional players in lipid and glucose metabolism, our finding opens up a door to better understand the molecular mechanisms along APOA4-LRP1 axis, whose dysregulation leads to obesity, cardiovascular disease, and diabetes.

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The neurorepellent, Slit2, prevents macrophage lipid loading by inhibiting CD36-dependent binding and internalization of oxidized low-density lipoprotein

Scientific Reports ◽

10.1038/s41598-021-83046-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Bushra Yusuf ◽

Ilya Mukovozov ◽

Sajedabanu Patel ◽

Yi-Wei Huang ◽

Guang Ying Liu ◽

...

Keyword(s):

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Super Resolution ◽

Low Density ◽

Dependent Manner ◽

Oxidized Low Density Lipoprotein ◽

Cortical Actin ◽

Cytoskeletal Remodeling ◽

Atherosclerotic Lesions ◽

Modified Lipoproteins

AbstractAtherosclerosis is characterized by retention of modified lipoproteins, especially oxidized low density lipoprotein (oxLDL) within the sub-endothelial space of affected blood vessels. Recruited monocyte-derived and tissue-resident macrophages subsequently ingest oxLDL by binding and internalizing oxLDL via scavenger receptors, particularly CD36. The secreted neurorepellent, Slit2, acting through its transmembrane receptor, Roundabout-1 (Robo-1), was previously shown to inhibit recruitment of monocytes into nascent atherosclerotic lesions. The effects of Slit2 on oxLDL uptake by macrophages have not been explored. We report here that Slit2 inhibits uptake of oxLDL by human and murine macrophages, and the resulting formation of foam cells, in a Rac1-dependent and CD36-dependent manner. Exposure of macrophages to Slit2 prevented binding of oxLDL to the surface of cells. Using super-resolution microscopy, we observed that exposure of macrophages to Slit2 induced profound cytoskeletal remodeling with formation of a thick ring of cortical actin within which clusters of CD36 could not aggregate, thereby attenuating binding of oxLDL to the surface of cells. By inhibiting recruitment of monocytes into early atherosclerotic lesions, and the subsequent binding and internalization of oxLDL by macrophages, Slit2 could represent a potent new tool to combat individual steps that collectively result in progression of atherosclerosis.

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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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Low-density-lipoprotein-receptor-related protein (LRP) interacts with a GTP-binding protein

Biochemical Journal ◽

10.1042/bj3360381 ◽

1998 ◽

Vol 336 (2) ◽

pp. 381-386 ◽

Cited By ~ 60

Author(s):

Lothar GORETZKI ◽

Barbara M. MUELLER

Keyword(s):

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Low Density ◽

Lipoprotein Receptor ◽

Dependent Manner ◽

Related Protein ◽

Gtp Binding ◽

Density Lipoprotein Receptor ◽

Dose Dependent ◽

Lipoprotein Receptor Related Protein

The low-density-lipoprotein-receptor-related protein (LRP) binds and internalizes numerous ligands, including lipoproteins, proteinase–inhibitor complexes and others. We have shown previously that LRP-mediated ligand internalization is dependent on cAMP-dependent protein kinase (PKA) activity. Here, we investigated whether ligation of LRP increases the intracellular cAMP level and PKA activity via a stimulatory GTP-binding protein. Treatment of LRP-expressing cell lines with the LRP ligands lactoferrin or urokinase-type plasminogen activator caused a significant elevation in cAMP and stimulated PKA activity in a dose-dependent manner. Addition of the 39 kDa receptor-associated protein (RAP), an antagonist for ligand interactions with LRP, blocked the lactoferrin-induced increase in PKA activity, demonstrating a requirement for ligand binding to LRP. Incubation of cell membrane fractions with lactoferrin increased GTPase activity in a time- and dose-dependent manner, and treatment with LRP ligands suppressed cholera-toxin-mediated ADP-ribosylation of the Gsα subunit of a heterotrimeric G-protein. Affinity precipitation of LRP with RAP resulted in co-precipitation of two isoforms of Gsα from detergent extracts. We thus conclude that LRP is a signalling receptor that associates directly with a stimulatory heterotrimeric G-protein and activates a downstream PKA-dependent pathway.

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Docosahexaenoic Acid, a Peroxisome Proliferator-Activated Receptor-α Activator, Induces Apoptosis in Vascular Smooth Muscle Cells by Activation of P38 Mitogen-Activated Protein Kinase

Hypertension ◽

10.1161/hyp.36.suppl_1.679-e ◽

2000 ◽

Vol 36 (suppl_1) ◽

pp. 679-679

Author(s):

Quy N Diep ◽

Rhian M Touyz ◽

Ernesto L Schiffrin

Keyword(s):

Smooth Muscle ◽

Cytochrome C ◽

Docosahexaenoic Acid ◽

Vascular Smooth Muscle ◽

Morphological Changes ◽

Mitogen Activated Protein Kinase ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Mitogen Activated Protein ◽

P38 Mapks

9 Omega-3 fatty acids (n-3 FAs) exert a blood pressure-lowering effect in hypertension, possibly by influencing vascular structure. We previously demonstrated that n-3 FAs might induce vascular smooth muscle cell (VSMC) apoptosis, which could exert an effect on structure of blood vessels. This study investigated signaling pathways through which n-3 FAs mediate apoptosis in VSMCs. Cultured Mesenteric VSMCs from Sprague Dawley rats were stimulated with docosahexaenoic acid (DHA), a representative n-3 FA. Morphological changes of apoptosis and DNA fragmentation were examined by phase-contrast microscopy and fluorescence microscopy with Hoechst 33342 staining. To clarify possible pathways of apoptosis, expression of phosphorylated p38 mitogen-activated protein kinases (p38 MAPKs), bax, bcl-2, cytochrome C and peroxisome proliferator-activated receptors-α (PPARs-α) was evaluated by Western blot analysis. DHA treatment induced cell shrinkage, cell membrane blebbing and apoptotic bodies in VSMCs. DHA increased apoptosis (%) in a time-dependent manner to 1.5±0.1, 3.6±0.5, 7.1±0.4, 22.5±0.6, 50.8±1.8 and 61.4±0.9 after 0, 1, 3, 6, 17, and 24 h, respectively. DHA time-dependently activated p38 MAPKs, bax, PPARs-α and cytochrome C with maximal effects obtained after 5, 30 min, 1 h and 3 h, respectively to 551±42, 245±55, 310±12 and 407±14.7 % of controls, respectively. SB-203580 (10 -5 M) and SB-202190 (10 -5 M), selective p38 inhibitors, reduced DHA-elicited apoptosis and expression of PPARs-α, but had no effect on expression of bax or cytochrome C. The present results indicate that DHA induces apoptosis in VSMCs through at least two distinct mechanisms: (i) a p38-dependent pathway that regulates PPAR-α and (ii) a p38-independent pathway via dissipation of mitochondrial transmembrane potential. The death-signaling pathway mediated by DHA may involve an integration of these multiple pathways. By triggering VSMC apoptosis, DHA could play a pathophysiological role in vascular remodeling in cardiovascular disease.

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