| Background：Hypertension is a common and frequently occurring disease, seriouslyendangering people’s health and quality of life. It is currently accepted that hypertensioncan cause vascular remodeling，leading to multiple organ damage and has become themost major cardiovascular risk factors. According to Epidemiological studies report,increasing of homocysteine (Hcy) in the blood was linked with coronary heart disease,a higher risk of stroke and peripheral vascular disease. It has been identified as apotentially important risk factors for cardiovascular disease. However, it is unclear howthe plasma HCY will affect vascular remodeling in hypertension.Endoplasmic reticulumstress (ERS) is a newly discovered pathway that leads to cell death, or apoptosis,participate in the occurrence and development of many diseases, such as diabetes,myocardial infarction, arteriosclerosis and dementia. The previous studies of the researchgroup have confirmed that hypertension can cause rat vascular smooth muscle cell ERS,and eventually lead to vascular remodeling. Then wether Hcy affect hypertensive ratsvascular smooth muscle cell ERS and result in hypertension increasing of vascular remodeling or not, there was no report. Enalapril Maleate and Folic Acid Tablets is acompound preparation, comprising Enalapril and Folic Acid Tablets in certainproportion.It is clinically proven that can significantly decrease the serum Hcyconcentration while lowering the blood pressure, has dual effect on the treatment of HHcypatients with hypertension and obvious synergistic effect in reducing cardiovascularevents. But whether Enalapril Folic Acid Tablets protect vascular smooth muscle cells andimprove vascular remodeling through inhibition of ERS or not, is not very clear now.This study established HHcy hypertensive rat model by feeding hypertensive ratsmethionine, and observed the expression of ERS signaling molecules GRP78and CHOPin the artery vascular smooth muscle cells and the change of Hcy concentration and medialvascular thickness, study the relationship between HHcy and hypertensive rats vascularsmooth muscle cells ERS,and the molecular mechanisms that leads to hypertensive ratsvascular remodeling increasing; Preliminary explore the effect that Enalapril Folic AcidTablets on hypertensive rats artery vascular smooth muscle cell ERS, provide newtherapeutic targets and theoretical basis for the final prevention and treatment of HHcywith hypertension and vascular remodeling which induced.Methods:This study first made hypertension rats model successfully by abdominalaortic stenosis, and established high homocysteine hypertension model by feedinghypertension rats model methionine particles. By using methods of rat tail-cuff,homocysteine detection, HE staining, immunohistochemical staining and stern blot, thisstudy observed:(1) Effects of HHcy on mean diastolic blood pressure (SBP) inhypertensive rats, serum homocysteine (Hcy) concentration and the influence of thethoracic aorta medial vascular thickness changes;(2) Effects of HHcy on the proteinexpression of GRP78and CHOP of vascular smooth muscle cells in hypertensive rats;(3)Effects of Enalapril Maleate and Folic on SBP in HHcy with hypertension rats,concentration of Hcy, thoracic aorta medial vascular thickness and the morphologicchanges of vascular smooth muscle cells;(4) Effects of Enalapril Folic Acid Tablets on theprotein expression of GRP78and CHOP of vascular smooth muscle cells in HHcy withhypertension rats. Results:（1）Blood increased gradually with time；the rats in the control group4W,subgroup8W mean SBP were162.32±7.72mmHg and170.64±8.97mmHg, comparedwith methionine group164.65±8.37mmHg and177.03±11.15mmHg, the subgroups of4W had no significant difference (P>0.05), but the differences were obvious between thesubgroups of8W，the methionine group was significantly higher than that of controlgroup(P<0.05).（2）The serum Hcy concentration increased gradually with time，thecontrol group4W and8W rats serum concentrations of Hcy were6.35±1.23μ mol/L and7.43±1.65μ mol/L; that of the methionine group rats were42.73±8.26μ mol/L and72.03±12.95μ mol/L, the methionine group was significantly higher than that of controlgroup (P<0.01).（3）the expression level of GRP78decreased gradually with time,reached a peak at4W，the optical density values of GRP78expression at4W and8W inthe methionine subgroup were0.83±0.035and0.66±0.027; the methionine subgroupwas higher than that in control group (0.65±0.025and0.56±0.031), and there wasstatistical significance (P<0.05);（4）the chop expression increased gradually with time,reached a peak at8W；OD values of at4W and8W in the methionine subgroup chopwere0.69±0.033and0.81±0.032, the differences were obvious, compared with thecontrol group (0.57±0.029and0.68±0.034),（5）the vessel wall thickened graduallywith time；at4weeks, the control group and methionine group rats the vascular smoothmuscle medial thickness were102.85±3.67μ m and109.02±3.79μ M,109.43±3.87μm and118.23±4.21μ M at8weeks. Methionine group rats medial vascular smoothmuscle thickness was significantly higher than the control group (P<0.05).（6）At4weeks, there were no significant differences between the control rats SBP (162.25±6.71mmHg) and methionine group SBP values (166.35±8.17mmHg)(P>0.05). EnalaprilFolic Acid Tablets group SBP values were130.78±6.97mmHg,decreased significantlycompared with the methionine group (P<0.05). At8weeks,the methionine group ratsSBP values178.53±9.66mmHg were significantly higher than the control group170.98±9.29mmHg (P<0.05). Enalapril Folic Acid Tablets group rats SBP values were140.56±5.36mmHg, had more significantly differences compared with methionine group(P<0.05).（7） Serum Hcy values of the rats in the4W and8W subgroup were6.45± 1.56μ mol/L and7.49±1.36μ mol/L,the methionine group serum Hcy values were41.65±8.27μ mol/L and71.93±10.36μ mol/L, Enalapril Folic Acid Tablets groupserum Hcy values were10.89±6.58μ mol/L and16.75±8.63μ mol/L. Methioninegroup Serum Hcy values were higher than those in the control group, differences weresignificant. Enalapril Folic Acid Tablets group were significantly lower than highmethionine group, there was statistical significance(P<0.01)（.8）The expression of GRP78is weaked gradually between groups. Expression was strongest at4weeks,then weaked at8weeks. OD values of GRP78expression in the control group, the methionine groupand Enalapril Folic Acid Tablets group4W,8W subgroups were:0.64±0.030,0.55±0.032,0.82±0.031,0.63±0.029,0.47±0.030,0.45±0.033. Expression of themethionine group was significantly higher than that of the control group (P<0.05), theexpression of Enalapril Folic Acid Tablets group was significantly lower than themethionine group (P<0.05).（9）The expression of CHOP is gradually enhanced betweengroups. expression started at4weeks,and show strongest at8weeks. OD values of chopexpression in the control group, the methionine group and Enalapril Folic Acid Tabletsgroup4W,8W subgroups were:0.56±0.029,0.67±0.031,0.68±0.030,0.84±0.034,0.46±0.032,0.49±0.033. Expressions of the methionine group were significantly higherthan that of the control group (P<0.05), the expression of Enalapril Folic Acid Tabletsgroup was significantly lower than methionine group (P<0.05).(10) The expression trendof GRP78decreased gradually, reached a peak at4weeks,then weakened at8weeks.Protein expression of GRP78in methionine4W and8W subgroups were0.87±0.05and0.67±0.04, Significantly higher than the control group0.79±0.03and0.46±0.05（P<0.05）. Protein expression of GRP78in Enalapril Folic Acid Tablets group were0.39±0.03and0.32±0.06, significantly lower than the methionine group.(P<0.05).(11)The expression of CHOP was inclined to strength gradually,and showed strongest signs at8weeks.Protein expression of CHOP in methionine4W and8W subgroups were0.67±0.032and0.91±0.04, Significantly higher than control group0.58±0.05and0.83±0.029,(P<0.05). Protein expression of CHOP in Enalapril Folic Acid Tablets groupwere0.36±0.06and0.48±0.055, significantly lower than methionine group.(P<0.05). （12） HE staining showed the control group and the methionine group rats vascularthickening, cell hypertrophy, arranged in disorder. Compared with the control group, themethionine group showed more obvious; compared with the methionine group,EnalaprilFolic Acid Tablets rats vascular thickening decreased significantly, smooth muscle cellhypertrophy symptoms improved obviously.（13）At the4w and8w,the control group andmethionine group rats vascular wall thickness were:102.96±2.91μ m,109.01±3.53μ mand109.76±3.09μ m,118.42±2.81μ M. Methionine group rats vascular wallthicknesses were significantly thicker than the control group (P<0.05). Enalapril FolicAcid Tablets rats vascular wall thicknesses were94.78±2.79μ m and97.03±2.96μ M,significantly thiner than the methionine group.Conclusion:（1）Serum Hcy concentrations and blood pressure values inmethioninediet group was significantly higher than the control group（.2）The expression level of ERSsignaling molecules GRP78and CHOP in methionine group was higher than that in thecontrol group..Early expression of GRP78dominated, the expression of CHOP dominatedwith the time.（3）Compared with the control group, the vascular media thickness of themethionine diet group was significantly thicker（.4）Compared with the methionine group,the blood pressure and the concentration of Hcy in Folic Acid Tablets rats significantlydecreased. Expression of smooth muscle cell ERS signaling molecules GRP78and CHOPdecreased significantly, medial vascular thickening decreased.In summary, homocysteine may induce hypertensive vascular smooth muscle cell theimbalance of ERS increased, induce protective factor ERS GRP78and CHOP expressionimbalance, vascular proliferation/apoptosis imbalance, vascular injuryworsenedworsened worsened, artery media thickening, and ultimately lead to vascularremodeling aggravated. And Enalapril Folic Acid Tablets may improve vascular injury,reduce artery media thickness, inhibit vascular remodeling. This study provides a newtheoretical basis for preventing vascular diseases induced by hypertension and HHcy. |
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