Influences Of IRE1? And P-JNK Expression On Vascular Remodeling In Hypertensive Rats With Hyperhomocystinemia And The Effect Of Enalapril Folic Acid Tablets Intervention

Research BackgroundHypertension is a chief risk factor which influence on mortality and morbidity of cardiovascular diease through its impact on target organs like the brain,heart,kidney and eyes.Hypertension-related end organ damage,such as transient ischemic attack and stroke,dementia,left ventricular hypertrophy and heart failure,angina and myocardial infarction,nephropathy,retinopathy and so on.Although the definitive cause of hypertension remains unknown at present,it is usually believed that genes and the environment,as well as their interactions,play an important role.Based on this gene-environment predisposition to hypertension,a lot of hypotheses have been put forward to explain the pathological mechanism and development of hypertension.Homocysteine(Hcy),a sulfur-containing amino acid,is an intermediate product of the body in the normal biosynthesis of the methionine and cysteine.The increased level of Hcy in plasma,usually called hyperhomocysteinemia(HHcy),is considered to be an independent risk factor for cardiovascular and cerebrovascular diseases.A causal link between homocysteine and blood pressure was supported by many experimental research.Animal studies report an increase in blood pressure induced by HHcy.Hcy elevate blood pressure may through complicated mechanisms,including its effect on vascular endothelial integrity.The study found that Hcy caused direct endothelial cell injury both in vitro and in animals.In addition,Hcy induced oxidative stress to endothelium,inhibit the generation of hydrogen sulfide(H2S)and reduced available nitric oxide(NO),a potent vasodilator.“Hypertension Prevention and Cure Guide Line of China”(2010)consider specifically Hcy as a risk factor for hypertension for the first time.At present,there are about 75% hypertension patients accompany with high Hcy in China,Chinese scholars denominate hypertension accompanied HHcy(Hcy?10?mol/L in serum)as “H” hypertension.The research found that Hcy can aggravate vascular remodeling caused by hypertension may be associated with high Hcy induce endoplasmic reticulum stress(ERS).ERS is a condition that the accumulation of unfolded/misfolded proteins after a variety of physiological and pathological,such as inflammation,oxidative stress,high glucose,calcium dysregulation,hypoxia,Hcy and so on.Transitory ERS would be advantageous to the function recovery of calcium homeostasis and protein folding,enhance the ability of cell resistance stress,but severe and persistent ERS can induce cell apoptosis.There are three different classes of ER stress protein have been identified,inositol-requiring protein-1(IRE1),protein kinase RNA(PKR)-like ER kinase(PERK)and activating transcription factor-6(ATF6).Various cardiovascular disorders,such as such as ischemic heart disease,cardiac hypertrophy,heart failure,atherosclerosis,hypertension and so on have been tested regarding the mechanisms of ERS.Studies have pointed out that the strategy of treatment of hypertension with HHcy,consideration should be given to the overall treatment adherence and economic benefit,thus the fixed-dose combination antihypertensive containing 0.8mg folic acid is recommended to “H” hypertension.Maleic acid enalaprilat folic acid tablets is an angiotensin convert enzyme inhibitors(ACEI)antihypertensive of fixed-dose combination,which is developed by China.It has dual function in lower blood pressure and Hcy,consequently reducing the risk of hypertension with high Hcy.However,the intervention effect and mechanism of enalaprilat folic acid tablets to vascular remodeling caused by hypertension with HHcy remains unknown.Research ObjectiveTo study the relationship between changes of IRE1? and p-JNK expression with hypertension rat with HHcy on vascular smooth muscle cells endoplasmic reticulum stress,and observe the effect of enalapril folic acid tablets reversal vascular remodeling.Thus provide researcher with theoretical foundation and strategy for the prevention and treatment of “H” hypertension.Research Meathods60 male SD rats underwent part abdominal aortic constriction(PAAC).Two weeks after operation,36 rats which SBP ?140mmHg(1mmHg=0.133kPa)were randomly divided into 3 groups.The control group was given normal diet and lavaged double distilled water;the model group was given 2.5% methionine diet and lavaged double distilled water;the enalapril folic acid tablets group was given 2.5% methionine diet and enalapril folic acid tablets[10mg/(kg·d)].Caudal arterial SBP and serum Hcy were measured when operation 2W,6W and 10W;After operation 10 W,morphological change of VSMCs were observed by HE,thoracic aorta intima-media thickness were measured by image analyses software,the expression level of thoracic aorta IRE1? and p-JNK protein were detected by immunohistochemistry and Western Blot.Research Results(1)2 Week after PAAC,the caudal arterial SBP and serum Hcy of the rats in thress groups were no difference,and the results were not statistically significant(P>0.05).(2)6 Week after PAAC,the caudal arterial SBP in model group were higher slightly than the control group(P>0.05),and the serum Hcy in control group were apparently lower than the model group(P <0.01).(3)10 Week after PAAC,compared with the control group,the model group rats caudal arterial SBP showed a significant rise,the serum Hcy were significantly higher and the thoracic aorta IMT were significantly incrassate(P<0.05).(4)10 Week after PAAC,the immunohistochemical staining score and the expression of IRE1? and p-JNK protein in model group were higher than those in the control group(P<0.05).(5)After the intervention of enalapril folic acid tablets,rats caudal arterial SBP,the serum Hcy and the thoracic aorta IMT were significantly lower than those in the model group(P <0.01);the immunohistochemical staining score and the expression of IRE1? and p-JNK protein were significantly declines than those in the model group(P<0.01).Research ConclusionThe PAAC increased the afterload of the rats and result in the endoplasmic reticulum stress of the vascular smooth muscle cells,the IRE1?and p-JNK protein were activated.The hypermethionine diet elevated the serum Hcy and increase the pro-apoptosis factors p-JNK,thus aggravate the endoplasmic reticulum stress of the vascular smooth muscle cells and vascular remodeling.After the intervention of enalapril folic acid tablets,rats caudal arterial SBP and the serum Hcy declined observably,thus inhibit the endoplasmic reticulum stress of the vascular smooth muscle cells.The expression of IRE1? and p-JNK protein were significantly declines,thus reversing the vascular remodeling.So we think the mechanism of HHcy aggravate the vascular remodeling of the hypertension rats may be connected with the endoplasmic reticulum stress protein IRE1?and p-JNK,enalapril folic acid tablets reverse vascular remodeling through inhibition of the expression of IRE1? and p-JNK protein.