Nutr Res Pract.  2017 Dec;11(6):445-451. 10.4162/nrp.2017.11.6.445.

Kimchi attenuates fatty streak formation in the aorta of low-density lipoprotein receptor knockout mice via inhibition of endoplasmic reticulum stress and apoptosis

• Woo M
• Kim M
• Noh JS
• Park CH
• Song YO

• KMID: 2395298
• DOI: http://doi.org/10.4162/nrp.2017.11.6.445

Abstract

BACKGROUND/OBJECTIVES
Endoplasmic reticulum (ER) stress is positively associated with atherosclerosis via elevating macrophage cell death and plaque formation, in which oxidative stress plays a pivotal role. Antioxidative, lipid-lowering, and anti-atherogenic effects of kimchi, a Korean fermented vegetable, have been established, wherein capsaicin, ascorbic acid, quercetin, 3-(4'-hydroxyl-3',5'-dimethoxyphenyl)propionic acid, and lactic acids were identified. In this study, mechanisms of action of kimchi methanol extracts (KME) on fatty streak formation via suppression of ER stress and apoptosis in aorta were examined in low-density lipoprotein receptor knockout mice.
MATERIALS AND METHODS
Mice fed a high cholesterol diet with an oral administration of KME (KME group, 200 mg·kg-bw⁻¹·day⁻¹) or distilled water (control group) for 8 weeks (n = 20 for group). Plasma lipid and oxidative stress levels were evaluated. Protein expression was measured by western blot assay. Fatty streak lesion size and the degree of apoptosis were examined in the aorta.
RESULTS
Compared to the control group, in the KME group, plasma lipids levels were decreased and oxidative stress was alleviated (P < 0.05). Protein expression levels of nuclear factor (erythroid-derived 2)-like 2-mediated antioxidants in aorta were increased whereas those for ER stress markers, glucose regulated protein 78, phospho-protein kinase RNA-like ER kinase, phospho-eukaryotic initiation factor 2 subunit α, X-box binding protein 1, and C/EBP homologous protein were decreased in the KME group (P < 0.05). Moreover, apoptosis was suppressed via downregulation of phospho-c-Jun N-terminal kinase, bcl-2-associated X protein, caspases-9, and -3 with a concomitant upregulation of anti-apoptotic protein, B-cell lymphoma 2 (P < 0.05). Fatty streak lesion size was reduced and the degree of apoptosis was less severe in the KME group (P < 0.05).
CONCLUSIONS
In conclusion, antioxidant activity of KME might prevent fatty streak formation through, in part, inhibition of ER stress and apoptosis in aortic sinus where macrophages are harbored.

Keyword

Endoplasmic reticulum stress; apoptosis; antioxidants; atherosclerosis; hypercholesteremia

MeSH Terms

Administration, Oral
Animals
Antioxidants
Aorta*
Apoptosis*
Ascorbic Acid
Atherosclerosis
bcl-2-Associated X Protein
Blotting, Western
Capsaicin
Carrier Proteins
Cell Death
Cholesterol
Diet
Down-Regulation
Endoplasmic Reticulum Stress*
Endoplasmic Reticulum*
Glucose
Hypercholesterolemia
Lactic Acid
Lipoproteins*
Lymphoma, B-Cell
Macrophages
Methanol
Mice
Mice, Knockout*
Oxidative Stress
Phosphotransferases
Plasma
Prokaryotic Initiation Factor-2
Quercetin
Receptors, Lipoprotein*
Sinus of Valsalva
Up-Regulation
Vegetables
Water
Antioxidants
Ascorbic Acid
Capsaicin
Carrier Proteins
Cholesterol
Glucose
Lactic Acid
Lipoproteins
Methanol
Phosphotransferases
Prokaryotic Initiation Factor-2
Quercetin
Receptors, Lipoprotein
Water
bcl-2-Associated X Protein

Figure

• 

  Fig. 1 Effects of KME on antioxidative transcription and enzymes in the aorta of LDL receptor knockout mice fed a high cholesterol diet for 8 weeks. Data are the mean ± SD (n = 10 per group). See the legend in Table 1 for descriptions of the control and KME groups. *Significant differences between two experimental groups are expressed as P-values calculated by Student's t-test (P < 0.05). KME, kimchi methanol extracts; Nrf2, nuclear factor (erythroid-derived 2)-like 2; SOD, superoxide dismutase; CAT, catalase; GSHPx, glutathione peroxidase.

• 

  Fig. 2 Effects of KME on endoplasmic reticulum stress in the aorta of LDL receptor knockout mice fed a high cholesterol diet for 8 weeks. Data are the mean ± SD (n = 10 per group). See the legend in Table 1 for descriptions of the control and KME groups. *Significant differences between two experimental groups are expressed as P-values calculated by Student's t-test (P < 0.05). KME, kimchi methanol extracts; GRP78, glucose regulated protein 78; p-PERK, phospho-protein kinase RNA-like ER kinase; p-eIF2α, phospho-eukaryotic initiation factor 2 subunit alpha; XBP1, X-box binding protein 1; CHOP, C/EBP homologous protein.

• 

  Fig. 3 Effects of KME on apoptosis-related molecules in the aorta of LDL receptor knockout mice fed a high cholesterol diet for 8 weeks. Data are the mean ± SD (n = 10 per group). See the legend in Table 1 for descriptions of the control and KME groups. *Significant differences between two experimental groups are expressed as P-values calculated by Student's t-test (P < 0.05). NS, no significance; KME, kimchi methanol extracts; p-JNK, phospho-c-Jun N-terminal kinase; Bax, bcl-2-associated X protein; Bcl-2, B-cell lymphoma 2; cIAP, cellular inhibitor of apoptosis protein.

• 

  Fig. 4 Oil red O and TUNEL staining of the aortic sinus of LDL receptor knockout mice fed a high cholesterol diet for 8 weeks. Data are the mean ± SD (n = 10 per group). Representative sections were stained with oil red O (magnification 40×) and TUNEL (magnification 400×). The apoptotic index was calculated by the following formula: 100 × [number of TUNEL-positive cell nuclei/total number of cell nuclei]. Arrows indicate TUNEL-positive cells. *Significant differences between two experimental groups are expressed as P-values calculated by Student's t-test (P < 0.05). KME, kimchi methanol extracts; TUNEL, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling.

• 

  Fig. 5 Mechanism for ER stress and apoptosis elucidated in this study. ER, endoplasmic reticulum; Bcl-2, B-cell lymphoma 2; Bax, bcl-2-associated X protein; IRE1, inositol requiring kinase 1; PERK, protein kinase RNA-like ER kinase; ATF6, activating transcription factor 6; cIAP, cellular inhibitor of apoptosis protein; p-JNK, phospho-c-Jun N-terminal kinase; XBP1, X-box binding protein 1; p-eIF2α, phospho-eukaryotic initiation factor 2 subunit alpha; CHOP, C/EBP homologous protein.

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