| Background:With the rapid economic growth and the extension of average age of the general population in our country, atherosclerosis has become a severe disease which is the major cause of heart, brain and body ischemia. Atherosclerosis disease is ranked the first lethality disease among all major diseases. According to the medical department status, nowadays, the cardiovascular patients have surpassed 150 millions and about 4 million patients die every year. Comparing the 24% mortality from the rest of the world, it is approximately 50% in our country and the trend is escalating. Among all the cardiovascular patients,75% fortunate survivors lose their ability of work, most patients carry stress disorder barrier and suffer from quality of lives damage. Furthermore, more cases show younger age group carrying the cardiovascular disease and the general public become more anxious. Over 10 billions Yuan has spent every year to treat patients who carry the cardiovascular disease and it creates a serious financial burden for our government and individuals. In order to reduce the overall financial charge and to improve the general public health condition, prevention and early discovery program is very essential and is advantageous in cuts the cardiovascular disease's formation rate, crippling rate and the lethality. Atherosclerosis implicates whole body blood vessel's group of pathological changes, for example the CHD, is the performance of human body blood vessel pathological change develops to the irreversible stage. The research indicated that the coronal atherosclerosis's occurrence development is a long process, under each kind of hazard factor function, from initial artery bast function barrier, artery stiff degree of hardness increase, to the naked eye obvious lipin stripe to the artery wall, develops for the artery gruel type mottling and blood vessel restructuring, finally creates the angiostenosis even is the mottling bursts or the thrombus forms causes the blood lumen to be completely unenlightened causes the cardiovascular event's occurrence, which involves the bast function to suffer injury, the artery elastic change, in film thickness increase and the inflammation participation and so on. Atherosclerosis (atherosclerosis, AS) pathogenesis's research had already experienced for more than one centuries. Mainly centers on 4 theories:The fatty infiltration theory, the blood platelet accumulation and the thrombus form the theory, the smooth muscle cell clone theory and the damage response theory, but detailed the pathogenesis has not been completely expounded still.The endothelin family has three kinds of isomers:endothelin 1, endothelin2, endothelin 3, and endothelin 1 biology activeness is the most diversest,and the research is also the most fullest. It is clear that the endothelinl was already including 21 amino acid active peptide, after G protein coupling acceptor A or acceptor B union, may activate the different signal passage, displays its biology effect finally. Endothelin 1(ET-1) was considered until now the strongest vasoconstriction peptide. Recently some research demonstrated:Bast element and many kinds of human diseases are related, including atherosclerosis, hypertension, the vasospasm, as well as the congested heart fades the cardiac muscle plump and remoulds. At hypertension and the coronary artery disease patient, its blood plasma ET-1 density elevates. In the gruel type mottling also discovered partially advances the ET-1 density, recognized as endothelial cell damage, shearing force, ischemia to blood vessel ET-1 produces increases. What is interesting, ET-1 and the endothelint system was considered that is disease and the health double-edged sword. On one hand, ET-1 lay between through blood vessel smooth muscle cell (VSMC) superficial ET acceptor Asia unit A(ETA) has led the cell multiplication and the vasoconstriction; On the other hand, lay between through the endothelial cell surface's ETB acceptor has led NO and the front row link element production and the vasodilatation. The ET-1 acceptor antagonist compound commonly used in the pulmonary artery high pressure and the malignant hypertension's treatment, it is not clear about atherosclerosis's influence; atorvastatin is the HMG-CoA reductases inhibitor, it may reduce TG effectively. At present many outside in vivo to test confirmed that atorvastatin to be possible to reduce ET-1 the expression, but it with the bast element acceptor antagonist compound union use, observes its influence to the gruel type hardening, at present has not been seen in related report yet. Statins is the 3-hydroxy-3-methylglutaric acid of COA reductase inhibitors. It makes the Synthetic cholesterol in hepatocyte has been inhibited, then result in the level of cholesterol decrease. Reduced morbidity and lethality in atherosclerosis. It had become the basic drugs on clinical therapy in atherosclerosis now. but it with the Endothelin acceptor antagonist compound union use, observes its influence to the atherosclerosis, at present has not been seen in related report yet. This experiment jointly and atorvastatin using the ET-1 acceptor antagonist compound, in the driven object and in vitro use immunity histochemistry, RT-PCR, ELISA, methods radioimmunoassay examines in separately the blood serum, atherosclerosis mottling and the cell the blood fats, ET-1, ICAM-1, VCAM-1, MCP-1, CRP, MMP9, NFkb expression, and probe into the effective with both theraphy in atherosclerosis at the same time.Objective:To evaluate the experiment effect of Endothelin-1 receptor antagonist and atorvastatin on serum liquid levels, inflammation factor expression and nucluer transcription factor in rabbit models of carotid atherosclerotic plaque in vivo, Such as changes in the level of LPS induced by vascular endothelial cell injury model in vitor. To evaluate the vascular endothelial cell vitality and ROS,and further analysis of endothelin-1,MMP-9,NF-KB gene expression level,study the mechanism.Method:Fourty male New Zealand and white rabbits were random divided into five groups: the control group(A=7), high cholesterol and artery balloon damage group(B=12), high cholesterol and artery balloon damage+endothelin-1 receptor antagonist subgroup(C=7), high cholesterol and artery balloon damage+atorvastin+endothelin-1 recetptor antagonis subgroup (D=7), high cholesterol and artery balloon damage+atorvastin+endothelin-1 recetptor antagonis treatment group (D=7), seven rabbits in each group,5 male New Zealand and white rabbits were random choosen from high cholesterol and artery balloon damage group, to observe the aorta atheromatous plaque formation. Blood and artery samples were collected at the end of 0,8 and 16 weeks for examination of serum liquid levels, such as hs-CRP,ICAM-1,VCAM-1,MCP-1 et. The expression of endothelin-1,MMP-9 and NF-KB were detected by immunohistochemistry and the expression of endothelin-1,MMP-9 and NF-KB mRNA detected by RT-PCR. In the level of LPS induced by vascular endothelial cell damaged model in vitro. The vascular endothelial cell were divided into five groups:the control group, LPS group, endothelin-1 receptor antagonist+Lps subgroup, endothelin-1 receptor antagonist+Lps+ atorvastatin subgroup and endothelin-1 receptor antagonist+Lps+atorvastatin treatment group; cells were collected at the end of 0,24h and 72h for examination cell vitality and ROS, at the same time, the expression of endothelin-1,MMP-9 and NF-KB mRNA detected by RT-PCR.Result:At the end of eight and sixteen weeks, compared with the control group, hematic content, endothelin-1 and serum inflammatory cytokines levels of rabbits fed with high cholesterol diet were higher(p<0.01) and nitric oxide reduced(p<0.01), compared with the high cholesterol and artery balloon damage group, hematic content, endothelin-1 and serum inflammatory cytokines levels of rabbits fed with another three groups were reduced(p<0.01) and nitric oxide enhanced(p<0.01), compared with the control group,Light section analysis of artery endometrial/than (membrane thickness, area), (135±0.87 0.40±0.01) (p<0.01); compared with high cholesterol and artery balloon damage group, the intima thickness in endothelin receptor antognist treatment group and atorvastin treatment group were much more decreased (135±2.61,1.40±0.180.44±0.01) (p<0.01), the expression of endothelin-1,MMP-9 and NF-KB was reduced in endothelin receptor antognist treatment group and atorvastatin treatment group in vivo and vitro.Conclusion:In all high cholesterol-fed and artery balloon damage group, serum TC,TG,LDL and HDL et. were increased remarkly, nitric oxide were decreased, the typical lipid streaks and early atheromatous plaque on the aorta have been formed, endothelin-1 receptor antognist and atorvastatin treatment group, reduce rabbit arteries after damaged balloon intimal ICAM-1, VCAM-1, MMP-9 expression, protecting endothelial function; ET-1 receptor antagonists and atorvastatin may inhibit NF-KB signaling pathways realize intravascular cells of protection. |
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