| Objective: Diabetes Mellitus (DM) is a chronic metabolic disease whichcharacterized by increased plasma glucose level. With the improvement ofpeople’s living standards, changes in lifestyle, and the rapidity of populationaging process, the prevalence of DM continues to rise worldwide whichcausing serious health problems and imposing a substantial economic burdenon societies. A national DM prevalence survey in2008showed that theprevalence of DM in20years of age or older in China was9.7%, accountingfor92.4million adults with diabetes. More than90%of them are type2diabetes mellitus (T2DM). Diabetic macroangiopathy is the leading cause ofdeath in diabetic patients, about80%of patients with type2diabetes died ofmacroangiopathy complications, such as storke, myocardial infarction, etc.The remarkable pathological change of diabetic macroangiopathy isatherosclerosis, DM can lead to premature and accelerated atherosclerosis.Several mechanisms have been shown to be involved in the development ofDiabetic macroangiopathy, however, the exact mechanism is not yet fullyunderstood. Recent insights support that the activation of p38mitogenactivated protein kinases (p38MAPK) pathway may constitute a commondownstream mechanism for Diabetic macroangiopathy. p38MAPK pathwaybelongs to the MAPK family, a stress activated serine/threonine protein kinase,which is the downstream target of proinflammatory cytokines and oxidativestress, closely associated with endothelial cell injury. Atorvastatin is asynthetic3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductaseinhibitor. In addition to its lipidlowering effects, atorvastatin has pleiotropiceffects including anti-atherogenic and anti-inflammatory actions.In the present study, we developed a rat model of type2diabetes to explore the relationship between phosphorylated p38MAPK (p-p38MAPK)and diabetic macroangiopathy and the intervention effect of atorvastatin.Methods:25healthy male wistar rats (4weeks old) were housed underspecific pathogen-free conditions at the Animal Facility of the3rd hospital ofHebei medical University. They were maintained on freely provided standardrodent chow and tap water. After one week of adaptive feed, All rats wererandomly divided into experiment group (EX, n=19) and normal control group(NC, n=6), the rats fed with standard rodent chow diet or high-fat, high-sugardiet,which composed of (by mg)20%sugar,10%lard,2.5%cholesterol,1%cholic and66.5%standard chow diet. Each rats remained on the assigned dietthroughout the whole experiment. Four weeks later, the EX group wasintraperitoneally injected with1%STZ (30mg/kg), The NC group wassimultaneously injected with sodium citrate buffer. Two weeks later, Tail veinblood glucose was measured, and those with blood glucose≥7.8mmol/L wereconsidered DM rats. The DM rats were randomly divided into two subgroups:diabetic control group (DM, n=7) and atorvastatin-treated diabetic group(ATR, n=8), Atorvastatin-treated group were treated with atorvastatin10mg·kg-1·d-1through intragastric administration for8weeks. Body weight wasmeasured weekly.At the end of the experiment, the rats were executed to collect blood andthoracic aorta, biochemical indicators TC, triglyceride (TG), LDL,high-density lipoprotein cholesterol (HDL), the level of intercellular adhesionmolecule1(ICAM-1), vascular cell adhesion molecule1(VCAM-1) andnuclear transcription factor (NF)-kappa B were detected. The proteinexpression of phosphorylated p38MAPK, NF-κB, and monocytechemoattractant protein-1(MCP-1) in the thoracic aorta was measure byimmunohistochemistry. All statistical analyses were conducted with the use ofSPSS software, version16.0.All the animal studies were conducted under a protocol approved by theInstitutional Research Animal Care Committee, and the Institute ReviewBoard of Hebei medical university granted ethical permission to this study. Result:1The general situation of ratsThe rats in NC group were in good condition, whose body weight showeda trend of increase, whereas there were no obvious change on diet and urinevolme in NC group.There were an increased trend of diet and urine volme inDM and ATR group, some of them had yellow, dark, messy, wet hair andweight loss.2Biochemical indexes of the rats2.1Indexes of the sixth weekenIn NC group, the FBG was6.50±0.52mmol/L, and in DM group theFBG was15.78±4.85mmol/L. FBG in DM group was significantly higher thanthat of NC group (P <0.01).2.2Biochemical indexes at the end of14weekNC: FBG6.33±0.69mmol/L, TG0.81±0.27mmol/L, TC2.18±0.39mmol/L, LDL1.24±0.47mmol/L, HDL1.55±0.33mmol/L, ICAM-175.63±19.52pg/ml, VCAM-1616.54±54.51ng/ml, NF-κB78.68±12.15μmol/L.DM: FBG12.99±2.07mmol/L, TG1.83±0.40mmol/L, TC4.15±0.41mmol/L, LDL2.53±0.44mmol/L, HDL0.68±0.23mmol/L, ICAM-1130.59±16.00pg/ml, VCAM-1990.19±119.18ng/ml，NF-κB170.22±21.53μmol/L.ATR: FBG12.43±2.40mmol/L, TG1.23±0.33mmol/L, TC3.07±0.51mmol/L, LDL1.86±0.28mmol/L, HDL0.98±0.33mmol/L, ICAM-1102.61±15.15pg/ml, VCAM-1809.29±150.27ng/ml, NF-κB116.13±32.63μmol/L.FBG was significantly higher in DM and ATR group than that of NCgroup (P <0.05), there was no difference in fasting blood glucose betweenDM and ATR group.The level of TG, TC, LDL, ICAM-1, VCAM-1, NF-κBwas significantly higher in DM and ATR group than that of NC group (P <0.05), after8weeks of Atorvastatin intervention, the level of TG, TC, LDL,ICAM-1, VCAM-1, NF-κB was significantly lower in ATR group than that of DM group (P <0.05). Compared with NC group, the level of HDL wassignificantly lower in DM and ATR group (P <0.05), after8weeks ofatorvastatin intervention, there was an increased trend of HDL.3Pathological changes of thoracic aorticNC group: Complete visible vascular endothelial cells, neat rows, intimalsmooth and neat membrane in smooth muscle cells.DM group: Visible aortic intimal thickening, swollen endothelial celldegeneration, the nucleus shrivel, intimal thickening, the elastic plate fracture,disordered arrangement of membrane in the smooth muscle cells and collagenfiber hyperplasia, outer membrane visible new capillariesATR group: Basic complete vascular endothelial cells, thickening of theintima encounters, membrane smooth muscle cells in the basic neatlyarranged.4Immunohistochemical resultsThe expression of p-p38MAPK, NF-κB and MCP-1was significantlyincreased in DM and ATR group than that of NC group (P <0.05). Chronicatrvostatin treatment (8weeks) greatly decreased the phosphorylation ofp38MAPK, NF-κB and MCP-1(P <0.05). The expression of NF-κB(r=0.406,P=0.001) and MCP-1(r=0.310, P=0.016) was highly correlated with p-p38MAPK.Conclusion:1Activation of p38MAPK pathway plays an important role in thedevelopment of diabetic macroangiopathy.2Atorvastatin can ameliorate diabetic macrovascular disease throughp38MAPK mechanism, and decrease vascular inflammation reaction. |
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