Atorvastatin ameliorate the expression of phosphorylated p38 mitogen-activated protein kinase in type 2 diabetic rats aorta

Abstract

Objective To explore the relationship between phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) and diabetic macroangiopathy, and the intervention effect of atorvastatin. Methods Total of 25 healthy male Wistar rats (4 weeks old) were randomly divided into experiment group (EX,n=19) and normal control group (NC,n=6) with random number table, the rats were fed with standard rodent chow diet or high- fat, high- sugar diet in the control and EX group. The rates in EX group were injected intraperitoneally with 1% streptozotocin(STZ) (30 mg/kg) and blood glucose≥7.8 mmol/L was considered as DM. The well- estabolished DM rats model were then randomly divided into two subgroups: diabetic control group (DM group,n=7) and atorvastatin-treated diabetic group (ATR group,n=8). The rats in ATR group were given intragastric administration of atorvastatin (10 mg · kg-1·d-1) for 8 weeks, and DM group was given drinking water in the same way. Body weight was measured weekly. The expression of phosphorylated p38 MAPK, neuclear factor(NF)-κB, and monocyte chemoattractant protein-1(MCP-1) in the thoracic aorta and blood lipids, intercellular cell adhesion molecule- 1(ICAM- 1), vascular cell adhesion molecule- 1(VCAM- 1) were measure by immunohistochemistry. The data were analyzed with SNK- q and Pearson correlation analysis. Results Structural destructions in DM rat aorta tissue were observed by HE staining, which characterized by endothelia cells swollen and degeneration and intima thickness. Smooth muscle disorders and collagen fiber hyperplasia in tunica media were also found in DM rats when compared to NC animals. All these pathological alterations can be improved by atorvastatin treatment. The expression of p-p38MAPK, NF-κB and MCP-1 was significantly increased in DM rats when compared to those in NC group ( Z= -3.466, -3.728, -3.832, P<0.05) and all these increasing were partly reversed by atorvastatin treatment( Z= -2.308, -2.160, -2.501, P< 0.05). The expression of NF-κB and MCP-1 were both found to be correlated with p-p38 MAPK levels( r=0.406, 0.310, both P<0.05). Compared with NC group, the levels of serum NF-κB, ICAM-1, VCAM-1, total cholesterol(TC), triglyceride(TG), and low-density lipoprotein(LDL) were significantly increased in DM group( t= -9.200, -5.586, -7.041, -8.788, -5.247, -5.142, all P< 0.05), whereas the level of high-density lipoprotein(HDL) decreased in DM group ( t=5.598, P<0.05). After 8 weeks of atorvastatin treatment, the serum levels of NF- κB, ICAM- 1, VCAM- 1, TG, TC, LDL were all significantly decreased compared to DM group( t=3.661, 3.360, 2.496, 4.348, 3.077, 3.446, all P<0.05). Conclusions Activation of p38 MAPK pathway plays an important role in the development of diabetic macroangiopathy. Atorvastatin may ameliorate diabetic macrovascular disease through activating p38 MAPK and decreasing vascular inflammation response. Key words: Diabetes mellitus, type 2; Atherosclerosis; Mitogen-activated protein kinase; Atorvastatin