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C-reactive protein/oxidised low-density lipoprotein/β2-glycoprotein I complex promotes atherosclerosis in diabetic BALB/c mice via p38mitogen-activated protein kinase signal pathway.

Zhang R, Zhou SJ, Li CJ, Wang XN, Tang YZ, Chen R, Lv L, Zhao Q, Xing QL, Yu DM, Yu P - Lipids Health Dis (2013)

Bottom Line: The mRNA expressions of receptors associated with lipid metabolism were quantified by real-time PCR.CRP/oxLDL/β2GPI complex dramatically promoted infiltration of SMCs, macrophages, and T cells, improved the mRNA expression of ABCA1 and ABCG1, but reduced the mRNA expression of SR-BI and CD36 and increased the phosphorylation of p38MAPK and MKK3/6 (all P < 0.05).The highest expression levels of IL-1, IL-9, PF-4, bFGF, and IGF-II were detected in the CRP/oxLDL/β2GPI group (P < 0.05).

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Diabetic Nephropathy Hemodialysis, Key Laboratory of Hormones and Development, Ministry of Health, Metabolic Diseases Hospital & Tianjin Institute of Endocrinology Tianjin Medical University, Tongan Street, Tianjin, Heping District 300070, China.

ABSTRACT

Background: The aim of this study was to investigate the effect of C-reactive protein/oxidised low-density lipoprotein/β2-glycoprotein I (CRP/oxLDL/β2GPI) complex on atherosclerosis (AS) in diabetic BALB/c mice.

Methods: BALB/c mice were fed high-fat and normal diet. Eight weeks later, the mice fed with high-fat diet were injected with streptozotocin (STZ) to induce diabetes. The diabetic mice were respectively injected twice monthly with 20 μg oxLDL, 20 μg β2GPI, 40 μg oxLDL/β2GPI complex, 44 μg CRP/oxLDL/β2GPI complex, and PBS. Aortas were stained with Sudan IV to investigate lipid plaque formation. The infiltration condition of smooth muscle cells (SMCs), macrophages, and T cells in the aortas were determined by immunohistochemistry (IH). The mRNA expressions of receptors associated with lipid metabolism were quantified by real-time PCR. The phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and MKK3/6 in aorta tissues were assessed by Western blot. The expression of inflammation cytokines was evaluated by protein chip.

Results: The lipid plaques were more extensive, the lumen area was obviously narrower, the ratio of intima and media thickness were increased, and the normal internal elastic lamia structure and endothelial cell disappeared (P < 0.05) in the oxLDL and CRP/oxLDL/β2GPI groups (P < 0.05). CRP/oxLDL/β2GPI complex dramatically promoted infiltration of SMCs, macrophages, and T cells, improved the mRNA expression of ABCA1 and ABCG1, but reduced the mRNA expression of SR-BI and CD36 and increased the phosphorylation of p38MAPK and MKK3/6 (all P < 0.05). The highest expression levels of IL-1, IL-9, PF-4, bFGF, and IGF-II were detected in the CRP/oxLDL/β2GPI group (P < 0.05).

Conclusions: CRP/oxLDL/β2GPI complex aggravated AS in diabetic BALB/c mice by increasing lipid uptake, the mechanism of which may be mediated by the p38MAPK signal pathway.

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Related in: MedlinePlus

Body weight of DM group and NC group. ●, DM group (n=120); ■, NC group (n=24). *P < 0.05, compared with group NC. Maintained on high-fat and sugar diet and standard chow diet, respectively, mice in DM group and NC group were weighed every week. Eight weeks later, DM group was intraperitoneally injected with 80 mg/kg 2% STZ three times for three consecutive days. The tail vein blood glucose was measured 72 h after the injection, and those with blood glucose ≥16.7 mmol/L were considered DM mice. The NC group was simultaneously injected with sodium citrate buffer. Two weeks later, the DM group was treated with oxLDL 20 μg, β2GPI 20 μg, oxLDL/β2GPI complex 40 μg, CRP/oxLDL/β2GPI complex 44 μg, and PBS, after which they were randomly divided into oxLDL group, β2GPI group, oxLDL/β2GPI group, CRP/oxLDL/β2GPI group, and PBS group, respectively (each group n=24). The same interventions were boosted four weeks later. NC group were injected with PBS at the same time. Four weeks later, blood was obtained via retro-orbital plexus and then sacrificed by cervical dislocation.
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Figure 1: Body weight of DM group and NC group. ●, DM group (n=120); ■, NC group (n=24). *P < 0.05, compared with group NC. Maintained on high-fat and sugar diet and standard chow diet, respectively, mice in DM group and NC group were weighed every week. Eight weeks later, DM group was intraperitoneally injected with 80 mg/kg 2% STZ three times for three consecutive days. The tail vein blood glucose was measured 72 h after the injection, and those with blood glucose ≥16.7 mmol/L were considered DM mice. The NC group was simultaneously injected with sodium citrate buffer. Two weeks later, the DM group was treated with oxLDL 20 μg, β2GPI 20 μg, oxLDL/β2GPI complex 40 μg, CRP/oxLDL/β2GPI complex 44 μg, and PBS, after which they were randomly divided into oxLDL group, β2GPI group, oxLDL/β2GPI group, CRP/oxLDL/β2GPI group, and PBS group, respectively (each group n=24). The same interventions were boosted four weeks later. NC group were injected with PBS at the same time. Four weeks later, blood was obtained via retro-orbital plexus and then sacrificed by cervical dislocation.

Mentions: After STZ injection, the mice in the DM group all became diabetic, but no animal died until they were sacrificed. After the mice were fed with high-fat and sugar diet for eight weeks, the body weight of the DM group became noticeably higher, which was different from that of group NC (P<0.05). The DM group significantly lost weight after STZ injection for three weeks compared with the NC group (P<0.05), then gradually gained weight because of continuous subsistence on high-fat diet (Figure 1). The blood glucose of the DM group was three times higher than that of the NC group (P<0.01).


C-reactive protein/oxidised low-density lipoprotein/β2-glycoprotein I complex promotes atherosclerosis in diabetic BALB/c mice via p38mitogen-activated protein kinase signal pathway.

Zhang R, Zhou SJ, Li CJ, Wang XN, Tang YZ, Chen R, Lv L, Zhao Q, Xing QL, Yu DM, Yu P - Lipids Health Dis (2013)

Body weight of DM group and NC group. ●, DM group (n=120); ■, NC group (n=24). *P < 0.05, compared with group NC. Maintained on high-fat and sugar diet and standard chow diet, respectively, mice in DM group and NC group were weighed every week. Eight weeks later, DM group was intraperitoneally injected with 80 mg/kg 2% STZ three times for three consecutive days. The tail vein blood glucose was measured 72 h after the injection, and those with blood glucose ≥16.7 mmol/L were considered DM mice. The NC group was simultaneously injected with sodium citrate buffer. Two weeks later, the DM group was treated with oxLDL 20 μg, β2GPI 20 μg, oxLDL/β2GPI complex 40 μg, CRP/oxLDL/β2GPI complex 44 μg, and PBS, after which they were randomly divided into oxLDL group, β2GPI group, oxLDL/β2GPI group, CRP/oxLDL/β2GPI group, and PBS group, respectively (each group n=24). The same interventions were boosted four weeks later. NC group were injected with PBS at the same time. Four weeks later, blood was obtained via retro-orbital plexus and then sacrificed by cervical dislocation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3643870&req=5

Figure 1: Body weight of DM group and NC group. ●, DM group (n=120); ■, NC group (n=24). *P < 0.05, compared with group NC. Maintained on high-fat and sugar diet and standard chow diet, respectively, mice in DM group and NC group were weighed every week. Eight weeks later, DM group was intraperitoneally injected with 80 mg/kg 2% STZ three times for three consecutive days. The tail vein blood glucose was measured 72 h after the injection, and those with blood glucose ≥16.7 mmol/L were considered DM mice. The NC group was simultaneously injected with sodium citrate buffer. Two weeks later, the DM group was treated with oxLDL 20 μg, β2GPI 20 μg, oxLDL/β2GPI complex 40 μg, CRP/oxLDL/β2GPI complex 44 μg, and PBS, after which they were randomly divided into oxLDL group, β2GPI group, oxLDL/β2GPI group, CRP/oxLDL/β2GPI group, and PBS group, respectively (each group n=24). The same interventions were boosted four weeks later. NC group were injected with PBS at the same time. Four weeks later, blood was obtained via retro-orbital plexus and then sacrificed by cervical dislocation.
Mentions: After STZ injection, the mice in the DM group all became diabetic, but no animal died until they were sacrificed. After the mice were fed with high-fat and sugar diet for eight weeks, the body weight of the DM group became noticeably higher, which was different from that of group NC (P<0.05). The DM group significantly lost weight after STZ injection for three weeks compared with the NC group (P<0.05), then gradually gained weight because of continuous subsistence on high-fat diet (Figure 1). The blood glucose of the DM group was three times higher than that of the NC group (P<0.01).

Bottom Line: The mRNA expressions of receptors associated with lipid metabolism were quantified by real-time PCR.CRP/oxLDL/β2GPI complex dramatically promoted infiltration of SMCs, macrophages, and T cells, improved the mRNA expression of ABCA1 and ABCG1, but reduced the mRNA expression of SR-BI and CD36 and increased the phosphorylation of p38MAPK and MKK3/6 (all P < 0.05).The highest expression levels of IL-1, IL-9, PF-4, bFGF, and IGF-II were detected in the CRP/oxLDL/β2GPI group (P < 0.05).

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Diabetic Nephropathy Hemodialysis, Key Laboratory of Hormones and Development, Ministry of Health, Metabolic Diseases Hospital & Tianjin Institute of Endocrinology Tianjin Medical University, Tongan Street, Tianjin, Heping District 300070, China.

ABSTRACT

Background: The aim of this study was to investigate the effect of C-reactive protein/oxidised low-density lipoprotein/β2-glycoprotein I (CRP/oxLDL/β2GPI) complex on atherosclerosis (AS) in diabetic BALB/c mice.

Methods: BALB/c mice were fed high-fat and normal diet. Eight weeks later, the mice fed with high-fat diet were injected with streptozotocin (STZ) to induce diabetes. The diabetic mice were respectively injected twice monthly with 20 μg oxLDL, 20 μg β2GPI, 40 μg oxLDL/β2GPI complex, 44 μg CRP/oxLDL/β2GPI complex, and PBS. Aortas were stained with Sudan IV to investigate lipid plaque formation. The infiltration condition of smooth muscle cells (SMCs), macrophages, and T cells in the aortas were determined by immunohistochemistry (IH). The mRNA expressions of receptors associated with lipid metabolism were quantified by real-time PCR. The phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and MKK3/6 in aorta tissues were assessed by Western blot. The expression of inflammation cytokines was evaluated by protein chip.

Results: The lipid plaques were more extensive, the lumen area was obviously narrower, the ratio of intima and media thickness were increased, and the normal internal elastic lamia structure and endothelial cell disappeared (P < 0.05) in the oxLDL and CRP/oxLDL/β2GPI groups (P < 0.05). CRP/oxLDL/β2GPI complex dramatically promoted infiltration of SMCs, macrophages, and T cells, improved the mRNA expression of ABCA1 and ABCG1, but reduced the mRNA expression of SR-BI and CD36 and increased the phosphorylation of p38MAPK and MKK3/6 (all P < 0.05). The highest expression levels of IL-1, IL-9, PF-4, bFGF, and IGF-II were detected in the CRP/oxLDL/β2GPI group (P < 0.05).

Conclusions: CRP/oxLDL/β2GPI complex aggravated AS in diabetic BALB/c mice by increasing lipid uptake, the mechanism of which may be mediated by the p38MAPK signal pathway.

Show MeSH
Related in: MedlinePlus