Effects Of Fasudil On Arteriosclerosis And Rho Kinase In Hypercholesterolemic

ObjectiveAtherosclerosis(AS)is a major cardiovascular disease pathology. ASis mediated by a variety of inflammatory mediators, which is the injuryperiod of a variety of chronic inflammatory response on arterial wall.This suggests that inhibition of AS is the useful strategy which canprevent the inflammation reaction of cardiovascular disease. Diabetes andAS are closely related, AS of diabetic patients occur earlier, moreseverely and the prognosis is poor.In this experiment, diabetic rats asexperimental subjects, by the intimal injury and high-fat diet, ASman-made model undergoing by diabetes rats, in order to observation ofAS-mediated formation of a variety of factors, including accumulation ofinflammatory cells, endothelial damage changes, and so on. Applying toRho kinase inhibitors-fasudil, investigates the effects of fasudil on ASand Rho/Rho kinase signal path in hyperchole sterolemic diabetic ratsmodel，and to observe its action mechanism．Methods1.Established diabetic rat models by STZ injection and then aortaintimal injury models were prepared using the diabetic model rat. 2.Trial groups: forty male Wistar Rats were divided into4groupsrandomly (10rats each group): a control group (common diet and saline),an AS group(intimal injury and high-fat diet and saline), a rosuvastataingroup (intimal injury and high-fat diet and rosuvastatain20mg/kg/d), anda fasudil group (intimal injury and high-fat diet and fasudil30mg/kg/d).All of the rats were intervened after12weeks different diet and killedafter two months different drugs application. The experiments wereapproved by the Ethics Committee of Fengtian Hospital Affiliated toShenyang Medical College.3.Bbefore and after drug intervention, The triglyceride (TG), totalcholesterol(TC),high density lipoprotein(HDL) and low densitylipoprotein (LDL) were detected in the blood samples.4. HE staining of the aortic arch: Specimens fixed in4%paraformaldehyde were stained by Hematoxylin and eosin stainingmethod, and the pharmalogical change were observed.5. In order to analyzed the mechanism of drugs, the levels ofVCAM-1、ICAM-1and Rho kinase mRNA were detected by RT-PCRmethod.6. Statistis Analysis: We used software SPSS11.5to analyze data. Allresults were represented (mean±SD). Measurement data were analyzedusing single factor analysis of variance. Comparison within subjectgroups were compared using the q test. A value of p <0.05was used for statistics significance.Results1.The results of blood lipid: It is similar in lipid levels before the testin each group, the difference was not statistically significant. Afterhigh-fat diet12weeks, compared with the control group, except HDLonly had decrease tendency, but no significant statistical difference, theother lipids index were significantly higher (P<0.05). After drugintervention2months, in rosuvastatin group, high-density lipoproteincholesterol only had increase tendency, but no significant difference, TC,TG and LDL levels were significantly lower compared with AS group (P<0.05), and fasudil group after2months intervention were no significantchanges in blood lipids (P>0.05).2.HE staining of the aorta results: In control group, endothelial cellordered and the smooth muscle cells arranged, no foam cells and lipiddeposition; In AS group,there were thickened intima, significantlygathered a large number foam cells in the intima, within the region ofmembrane junction disordered, the internal elastic membrane migratedtowards to the intimal; The rosuvastatin group and the fasudil groupreduced intimal thickening, decreased foam cells and improved smoothmuscle cell disorder significantly.3.The expression of mRNA of VCAM-1,ICAM-1and Rho kinase:The expressions of VCAM-1, ICAM-1, Rho-kinase mRNA were very weak in aortic wall tissue of control group. Their expressions weresignificantly increased in AS group (P <0.05). Copmared with AS group,they were decreased significantly in simvastatin group and fasudilgroup．Fasudil had similar anti-atherogenetic effects as Simvastatin buthad no influence on plasma lipid.ConclusionsFasudil could attenuate AS in this hyperchololesterolemic rats modelwhich might be attributed to its anti-inflammatory effects induced byRho/Rho kinase signal transduction pathway.