| BackgroundThe metabolic syndrome(MS)is a world-wide epidemic disease and consists of the combined presentation of multiple cardiovascular risk factors that include abdominal obesity,glucose intolerance,insulin resistance,hyperinsulinemia,hypertension and dyslipidemia.The overall risk of MS is more than the sum of the risk of its sole components,they maybe reinforced each other.Therefore,it is of great importance to understand the pathogenesis of MS and to detect the patients who are at higher risk of type 2 diabetes and cardiovascular disease.Clinical studies have demonstrated that the prevalence of atherosclerosis is significantly increased in MS patients,and even in young adults MS is also the risk factor for atherosclerosis.These results suggested that vascular structural and functional changes are the basis of cardiovascular disease in patients with MS.But at present,little is know about macro-vascular structural and functional changes in MS.Compared with the controls,patients with MS showed increased serum C-reative protein,interlukin-6,tumor necrosis factor-αand interlukin-18.Animal studies have demonstrated that the mRNA of interlukin-6,monocyte chemoattractant protein-1 was elevated in the kindey of rats with MS.Based on these interesting and significant findings,we can infer that inflammation may play a pivotal role in the development of MS.However,those results can not render us to differentiate whether inflammation is a 'risk marker' or a 'risk factor'of MS.Interlukin-18(IL-18)is an important inflammatory mediator that regulates immune response and inflammatory reaction.The role of IL-18 in cardiovascular disease is an attracting topic for the researchers.The expression of IL-18 and IL-18 receptor was up-regulated in carotid atherosclerotic plaque in patents with stable and unstable angina pectoris,and the level of IL-18 mRNA was associated with plaque instability.IL-18 enhances atherosclerosis in ApoE deficiency mice,whereas IL-18 knockout prevent the progression of atherosclerosis.Serum IL-18 was elevated in obese subjects,and epidemic study revealed that IL-18 is the independent risk factor for MS.Taken together these results implied that IL-18 play an important role in MS especial in macro-vascular structural and functional alterations.Thus we hypothesized that macro-vascular structural and functional changes, especially enhanced vascular inflammation is the underlying mechanism for cardiovascular complication in MS patients,and IL-18 accelerate the progression of MS and particularly enhance macro-vascular inflammatory reaction.This study aimed to elucidate whether inflammation is a 'risk marker' or a 'risk factor' of MS,and to provide evidence for a better understanding of MS.Objective1.To observe whether there are aortic structural abnormalities and vascular inflammation in rat with MS.2.To clarify the influence of IL- 18 on the progression of MS,particularly focused on the effect of IL-18 on vascular inflammation.3.To study the mechanism which underlying the role of IL-18 in vascular inflammatory reaction in MS.Method1.Cloning of rat IL- 18 and constructing of IL- 18 adenovirus vector Based on the rat IL-18 sequence in Genebank,we designed one pair of primers. Using total RNA extracted from rat spleen and reverse transcript polymerase chain reaction,we cloned the CDS sequence of rat IL-18.After the cloned IL-18 was sub-cloned to T vector and sequenced,the Ad-Easy system was used to construct adenovirus containing rat IL-18.293-T cells were infected with the IL-18 plasmid. Recombinant adenovirus from a single plaque was expanded and purified,viral titer was determined by plaque assay.2.Macro-vascular lesions and the role of Interlukin-18 in vascular inflammation Fifty male Wistar rats were randomly divided into control group(n=12)and MS group(n=38).Control rats were fed with standard chow and tap water,MS rats were fed with standard chow plus high-fructose(10%,w/v)water.After high fructose feeding for 32 weeks,MS rats were further divided into three groups,MS group(n=9),continuing of high fructose feeding;vehicle group(n=9),continuing of high fructose feeding plus injection of 1×1010pfu adenovirus only contain GFP by tail veins;IL-18 vector group (n=13),continuing of high fructose feeding plus injection of 1×1010pfu IL-18 adenovirus by tail veins.Rats of control and MS groups were injected with the same volume of PBS by tail veins.After adenovirus transfection for 6 weeks,all the rats were killed and the aortas were harvested and kept at -80℃.The follwing parameters were measured during the study:(1)2 ml blood was drawn from the jugular sinus of all the rats before and after fructose feeding and after transfection with IL-18 adenovirus for 6 weeks,serum was separated and using routine method to measuring lipid,glucose and insulin;(2)1,2,3,4,and 6 weeks after the IL-18 adenovirus transfection,all the rats have their blood drawn from jugular sinus for measuring serum IL-18;(3)body weight and their tail blood pressure measured once per week;(4)before sacrifice,cardiac catheter was performed and SBP,DBP were measured in all the rats.At the end of the experiment,all the animal was sacrificed,the aortas were kept for the following study:(1)pathological study of aorta;(2)verhoeff elastic fibers stain; (3)real-time RT-PCR measurement of IL-18,ICAM-1 and VCAM-1 mRNA;(4) immunohistochemistry of aortic IL-18,ICAM-1,VCAM-1 and macrophages;(5) Western Blot for IL-18,ICAM-1,VCAM-1 and IRAK-1;(6)EMSA for measuring NF-κB acticity.Results1.Cloning of rats IL-18 and constructing IL-18 adenovirusWe have successfully cloned rat IL-18,and its sequence was identical to the rat IL-18 sequence in Genebank.Using Ad-Easy system,we constructed rat IL-18 adenovirus,the vehicle containing only GFP was also constructed.2.Macro-vascular lesions and the role of IL-18 in vascular inflammation in MS2.1 The experimental animalsSeven rats of MS group died during the entire experiment,no rat died in control group.43 rats finished the study,12 rats in control group,9 rats in MS group,9 rats in vehicle group and 13 rats in IL-18 vector group.2.2 Comparison of metabolic indexes between control and MS group after fructose feedingThere is no significant difference in terms of body weight,tail blood pressure, glucose,lipids and insulin before fructose feeding.After feeding with fructose for 32 weeks,body weight,tail blood pressure,triglyceride,insulin and HOMA were significantly increased in MS group than in control group,whereas glucose and total cholesterol showed no difference.This indicated that the rat model of MS was achieved by feed high fructose diet for 32 weeks.2.3 Changes of serum IL-18 after adenoviral transfectionSerum IL-18 was significant increased in MS group before IL-18 adenovirus transfection.After IL-18 adenovirus transfection,serum IL-18 was further increased in IL-18 vector group than in vehicle group at 1 week,the serum concentration of IL-18 reached its summit after 2 weeks transfection,and its level was 4 fold higher than vehicle group(256.53±25.32 vs.60.93±6.57 pg/ml,P＜0.0001).Serum IL-18 begin decrease at the end of the third week(153.17±29.41 vs.59.67±8.57 pg/ml,P＜0.0001), and at the end of 4-week,serum level of IL-18 vector group was similar to that of vehicle group(64.40±2.93 vs.56.62±8.46 pg/ml,P=0.070).2.4 Effect of IL-18 on metabolic parameters in ratsAfter IL-18 transfection for 6 weeks,insulin and HOMA were significantly increased in IL-18 vector group compared to vehicle group(P＜0.001,P＜0.05);other parameters showed no significant difference.Insulin and HOMA were significantly increased in IL-18 vector group after transfection for 6 weeks compared to the levels of insulin and HOMA before transfection(P＜0.001,P＜0.05);other parameters showed no significant difference.2.5 Comparison of invasive Blood pressure among four groupsAt the end of the experiment,invasive blood pressure was obtained from all the rats.SBP and DBP were significantly increased in MS group,vehicle group and IL-18 vector group when compared with control rats,but pulse pressure showed no difference among four groups.2.6 Comparison of morphological and ultra-structural index of aortaHE stain demonstrate that the intima of rats in control group,MS group and vehicle group was smooth,the endothelial cells were flat and attached to the internal elastic lamina;the intima of IL-18 vector group was coarse,there are breakages of endothelial cells.Compare to control group,MS rats showed significant increase of MCSA,Mt, WLR(P＜0.05～＜0.001);LCSA,ECSA,Ld and Vd showed no difference.Compared to vehicle group,Le,Mt,WLR were significantly increased in rats of IL-18 vector group(P＜0.01～＜0.001).Compared to MS group,Mt,WLR were significantly increased in rats of IL-18 vector group(P＜0.0～0.001).Compared to controls,MCSA,Le,Mt,WLR were significantly increased in rats of IL-18 vector group(P＜0.05～＜0.001).2.7 Result of real-time RT-PCRThe levels of IL-18 mRNA were increased in MS group and vehicle group than in controls(1.96±0.16 vs.1.03±0.26;1.87±0.25 vs.1.03±0.26,all P±0.001);the expression of IL-18 mRNA was significantly increased in IL-18 vector group than in vehicle group(2.59±0.69 vs.1.87±0.25,P＜0.001).Compared to control group,the levels of ICAM-1 and VCAM-1 mRNA were increased in MS group and vehicle group(P＜0.05～0.001);the levels of ICAM-1 and VCAM-1 were further increased in IL-18 vector group than in vehicle group(ICAM-1: 2.85±0.89 vs.1.79±0.79,P＜0.01;VCAM-1:4.26±0.68 vs.2.49±0.39,P＜0.001).2.8 Results of immunohistochemistryThe level of IL-18 protein was lower in control group,and was significantly increased in MS group and vehicle group.Compared to three other groups,IL-18 levels were further increased in IL-18 vector group.IL-18 was abundant in intima and was also presented in medium.The levels of ICAM-1 and VCAM-1 protein were lower in control group,and were significantly increased in MS group and vehicle group.Compared to three other groups, ICAM-1 and VCAM-1 levels were further increased in IL-18 vector group,and ICAM-1 and VCAm-1 were abundant in intima and was also presented in medium.CD68 positive cells were rare in control group(0-1 cell per visual field);CD68 positive cells were increased in MS group and vehicle group(7.15±1.34 vs.0.59±0.28, P＜0.001;6.71±0.59 vs.0.59±0.28,P＜0.001).CD68 positive cells were significantly increased in IL-18 vector group than in other groups(11.29±2.38 vs.6.71±0.59, P＜0.001;11.29±2.38 vs.7.15±1.34,P＜0.001;11.29±2.38 vs.0.59±0.28,P＜0.001).2.9 Results of Western BlotWestern Blot revealed that IRAK-1,ICAM-1 and VCAM-1 were higher in MS group and vehicle group than in control group(P＜0.05～0.001);IRAK-1,ICAM-1 and VCAM-1 were increased in IL-18 vector group than in other groups(P＜0.01～0.001).2.10 NF-κB activityEMSA was used to measure NF-κB activity among four groups.NF-κB activity was increased in IL-18 vector group than in other groups,and was increased in MS group and vehicle group than in controls. 2.11 Result of analysis of correlationPerason correlation analysis revealed that ICAM-1 and VCAM-1 were correlated with body weight,tail blood pressure,insulin,HOMA,Mt and WLR.Conclusion1.We have constructed rat IL-18 adenoviral vector successfully,which provide a tool for us to making further study on the role of IL-18 in cardiovascular disease.2.Rats model of MS that mimic human MS can be achieved by feeding Wistar rat high fructose water(10%,v/w)for 32 weeks.3.MS rats showed hypertrophical remodeling of aorta and the vascular inflammation was enhanced in aorta of MS rats.All these abnormalities maybe involved in the high prevalence of cardiovascular complication in MS.4.IL- 18 increase insulin and aggravate insulin resistance in MS rats.5.IL-18 enhanced aortic remodeling and inflammation in MS rats through IRAK- 1/NF-κB dependent pathway. AbstractBackgroundThe prevalence of MS is increased in developed and developing countries as a result of improved living standard. Epidemiologic study found that in Chinese adult, the crude prevalence of MS was 16.5% and the age-standardized prevalence of MS was 10.0% in men and 23.3% in women. Furthermore, the prevalence of the MS was higher in northern than in southern China, and higher in urban than rural residents. MS is a cluster of multiple risk factors in one individual, the major complications of MS is coronary heart disease, diabetes and atherosclerosis. Recent studies indicated that the effect of each component of MS is rather than it sole addition effect, they can enhanced each other. Therefore, further studies are needed to reveal the pathogenisis and the effect of each component of MS in order to prevent and treat patients with MS.The definition of MS changed as our knowledge about MS deepened gradually. Although there is difference in each criterion, they all include obesity, hypertension, dyslipidemia and abnormality in glucose metabolism. The component of MS changed gradually, hypertension is always the major disorder of MS, this is because the prevalence of hypertension is very high in patients with MS. Overweight and obesity are closely related with MS, and is considered as the major risk factor of MS. Because overweight and obesity is correlated with other component of MS, on the other hand, endocrinal disorder in overweight and obesity aggravate MS by different mechanism, especially in central obesity. Obesity is considered to be major component of MS now.Clinical studies have demonstrated that left ventricular dimension, ventricular wall and left ventricular mass increased and ventricular systolic and diastolic function impaired in patients with MS. Left ventricular mass increased and ventricular function impaired in hypertensives with MS. These results suggested that cardiac structural and functional abnormalities is evident in patients with MS, this maybe involved in the cardiovascular complication in those patients. Ventricular function was sustained by myocardial contraction and relaxation and the synchronicity of ventricular segments. Left ventricular systolic and diastolic synchronicity was impaired in hypertensive patients, and ventricular dyssynchrony was also existed in patients with diastolic heart failure. As hypertension and left ventricular hypertrophy are the common causes of diastolic heart failure, it is of great interest to study left ventricular function and ventricular synchronicity in hypertensive patients with overweight or obesity, LVH and ventricular arrhythmias.In summary, as hypertension and obesity are major abnormalities of MS, and also the common reason for cardiac dysfunction. Ventricular synchronicity is important for ventricular function. We hypothesized that left ventricular function and synchronicity are impaired in hypertensive patients with overweight or obesity. In order to test our hypothesis, this study included mild-to-moderate hypertensive patients, and using tissue Doppler imaging (TDI) measured myocardial velocity and synchronicity in different left ventricular segments. To elucidate the influence of obesity, LVH and ventricular arrhythmia on left ventricular function and synchronicity, we divide our patients into different study group acording to different criterion.Objective1. To observe the abnormalities of left ventricular function and synchronicity in hypertensive patients;2. To elucidate the influence of obesity, LVH and ventricular arrhythmias on left ventricular function and synchronicity in hypwertensive patients.MethodsWe selected 125 patients with mild-to-moderate hypertension, 30 patients with hypertension and ventricular arrhythmias and 32 normal subjects for this study. Two dimensional, M mode, pulse Doppler and tissue Doppler imaging echocardiography was performed in all subjects. A 12-segement model was used. Sm, Em and the mean of Sm and Em of six basal segments were measured to reflect left ventricular systolic and diastolic function. Systolic and diastolic asynchrony was determined by measuring time to peak of Sm (Ts) and time to peak of Em (Te), the maximal differences in Ts (Ts-max) and Te (Te-max) between any two of the left ventricular segments and the standard deviation of Ts (Ts-SD) and Te (Te-SD) of all 12 segments. Results1. Impaired left ventricular function and synchronicity in hypertensive patients with overweight and obesityUsing BMI>24.0 as overweight and >28.0 as obesity diagnostic criteria. Patients whose data are not sufficient and normal subjects with BMI>24.0 were excluded. After matched for age, there are 28 normal subjects and 115 hypertensives were final analyzed, those including 42 patients only with hypertension, 50 patients with hypertension and overweight, 23 patients with hypertension and obesity. All the parameters between patients with overweight and patients with obesity showed no differences except for BMI, we put those 73 patients together and named hypertensive patients with overweight and obesity.1.1 Clinical characteristics of the study populationsSBP, DBP and TG were significantly increased in patients with hypertension and hypertensive patients with overweight and obesity when compared with controls, and HDL-C was decreased in patients groups than in controls. BMI was higher in hypertensive patients with overweight and obesity when compared with hypertensive patients. Other parameters showed no significant difference among three groups.1.2 Echocardiographic parameters among three groupsLVPWd, LVMI, and A wave velocity were significantly increased in patients with hypertension and hypertensive patients with overweight and obesity when compared with controls. E/A was decreased in patients groups than in controls. LVIDd was increased and mean Sm decreased in hypertensive patients with overweight and obesity when compared with controls.1.3 Comparison of left ventricular function among three groupsSm and Em were significantly decreased in hypertensive patients with overweight and obesity when compared with controls (P<0.05-0.01). Mean Em and Em/Am were significantly decreased in hypertensive patients and hypertensive patients with overweight and obesity when compared with controls (Em: 5.81±1.98 vs. 7.21±1.62 cm/s, P<0.01; 5.19±2.03 vs. 7.21±1.62 cm/s, P<0.001; Em/Am: 1.02±0.45 vs. 1.45±0.67, P<0.01; 0.87±0.46 vs. 1.45±0.67, P<0.001).Sm, Em, mean Sm and Em/Am were decreased in hypertensive patients with overweight and obesity compared with hypertensive patients (Mean Sm: 5.16±1.07 vs. 5.69±1.24 cm/s, P<0.05; Em/Am: 0.87±0.46 vs. 1.02±0.45, P<0.05). Ts, Ts-max and Ts-SD were significantly prolonged in hypertensive patients and hypertensive patients with overweight and obesity when compared with controls (P<0.05-0.001). Ts and Ts-max were significantly increased in hypertensive patients with overweight and obesity compared with hypertensive patients (P<0.05-0.001).Te-max was significantly prolonged in hypertensive patients and hypertensive patients with overweight and obesity when compared with controls (all P<0.001). Te-SD was significantly increased in hypertensive patients when compared with controls (44±3 vs. 39±3 ms, P<0.001). Te-SD was decreased in hypertensive patients with overweight and obesity when compared with hypertensive patients (41±2 vs. 44±3 ms, P<0.01). There is no significant difference of Te-max among three groups.1.5 Analysis of correlation in hypertensive groupsMean Sm was negatively correlated with BMI, LVMI. Mean Em was positively correlated with E and negatively with BMI and age. Ts-max was positively correlated with BMI and LVMI. Te-max was positively correlated with duration of hypertension and LVMI and negatively correlated with mean Em.2. Impaired left ventricular function and synchronicity in hypertensive patients with ventricular hypertrophyLeft ventricular hypertrophy (LVH) was defined as LVMI>150g/m2 for man and >120g/m2 for women. Patients whose data are not sufficient were excluded. After matched for age, there are 30 normal subjects and 115 hypertensives were final analyzed, including 84 NLVH patients and 31 LVH patients.2.1 Clinical characteristics of the population studiedThere is no difference in terms of age, sex, heart rate and width of QRS among three groups. SBP, DBP and BMI were significantly increased in NLVH and LVH groups when compared with controls.2.2 Echocardiographic parameters among three groupsLVPWd, FVSd, LVMI, and A wave velocity were significantly increased, and E/A, mean Em and Em/Am were decreased in NLVH and LVH group when compared with controls. LVIDd, LVPWd, IVSd and LVMI were increased in LVH group when compared with NLVH group.2.3 Comparison of left ventricular function among three groupsSm, Em, mean Em and Em/Am were significantly decreased in NLVH group and LVH group when compared with controls (P<0.05-0.001).Sm, mean Sm, Em and mean Em were significantly decreased in LYH groups when compared with NLVH group (P<0.05-0.001).2.4 Comparison of left ventricular synchronicity among three groupsTs, Ts-max and Ts-SD were significantly prolonged in NLVH and LVH group when compared with controls (P0.05-0.001). Ts and Ts-max were significantly increased in LVH group when compared with NLVH group (P<0.05-0.01).Te-max was significantly prolonged in NLVH and LVH group when compared with controls (all P<0.001). Te and Te-max were significantly increased in LVH group when compared with NLVH group (P<0.05-0.001).2.5 Analysis of correlation in hypertensive groupsTs-max was positively correlated with LVMI, and negatively with mean Sm. Te-max was negatively correlated with E, Em and Em/Am.2.6 The prevalence of left ventricular dyssychrony in NLVH and LVH groupUsing a normal cut-off value of more than 84 ms for Tsmax, 71.0% LVH patientsand 37.2% NLVH patients showed prolonged Ts-max (chi-squared 10.45, P=0.001). Similarly, using a cut-off value of more than 73 ms for Te-max, 29% LVH patients and 10.7% NLVH patients had significantly prolonged Te-max and thus evidence of diastolic asynchrony (chi-squared 5.76, P=0.02).2.7 The diagnostic value of Ts-max and Te-amxThe ability of Ts-max and Te-max to detect hypertensive patients with LVH was assessed by using ROC curve. The area under the curve of Ts-max was 0.691 [95% confidential interval (CI) 0.582-0.800]. A Ts-max value of more than 88 ms had 68% sensitivity and 71% specificity for detecting hypertensive patients with LVH, but Te-max showed a poor ability to detect LVH patients, and the area under the curve of Te-max was 0.590 (95% CI 0.477-0.704).3. Impaired left ventricular function and synchronicity in hypertensive patients with ventricular arrhythmiasPatients with family history of cardiac arrhythmias and have arrhythmias during echocardiographic examination were excluded. Patients whose data are not sufficient were also excluded. After matched for age, there are 32 normal subjects and 74 hypertensive patients and 30 hypertensive patients with ventricular arrhythmias were final analyzed.3.1 Clinical characteristics of the study populationsThere is no significant difference in terms of age, sex, heart rate and width of QRS among three groups. SBP, DBP and BMI were significantly increased in hypertensive patients and hypertensive patients with ventricular arrhythmias when compared with controls. Mean duration of arrhythmia was 20±11 monthes. The mean number of ventricular arrhythmias in patients who underwent Holter monitoring was 4,676 beats. 13% patients had taken anti-arrhythmia drugs.3.2 Echocardiographic parameters among three groupsLVPWd and A wave velocity were significantly increased, and E/A was decreased in hypertensive patients and hypertensive patients with ventricular arrhythmias when compared with controls. IVSd was increased in hypertensive patients with ventricular arrhythmias than in controls.3.3 Comparison of left ventricular function among three groupsSm, Em were significantly decreased in hypertensive patients and hypertensive patients with ventricular arrhythmias when compared with controls (P<0.05-0.001). Mean Em, Em/Am and mean Sm was decreased in hypertensive patients with ventricular arrhythmias when compared with controls.Sm, Em were significantly decreased in hypertensive patients with ventricular arrhythmias when compared with hypertensive patients (P<0.05-0.01).3.4 Comparison of left ventricular synchronicity among three groupsTs, Ts-max and Ts-SD were significantly prolonged in hypertensive patients and hypertensive patients with ventricular arrhythmias when compared with controls (P<0.05-0.001). Ts, Ts-max and Ts-SD were significantly increased in hypertensive patients with ventricular arrhythmias when compared with hypertensive patients (P<0.05-0.01).Te, Te-max and Te-SD showed no differences among three groups.3.5 Analysis of correlation in hypertensive groupsSub-analysis in hypertensive patients with ventricular arrhythmias revealed that Ts-max was positively correlated with the duration of ventricular arrhythmias and LVMI. There were no other significant correlations between parameters of LV systolic synchronicity and age, heart rate, blood pressure, and color Doppler parameters.3.6 The diagnostic value of Ts-max and Te-amxThe ability of Ts-max to detect hypertensive patients with ventricular arrhythmias was assessed by using an ROC curve. The area under the ROC curve was 0.658 (95% confidential interval, 0.543-0.772). A Ts-max value of 70 ms had 90% sensitivity and 33% specificity for detecting hypertensive patients with ventricular arrhythmia, while Te-max showed a poor ability to detect hypertensive patients with ventricular arrhythmia.Conclusion1. Left ventricular systolic and diastolic function and synchronicity were impaired in hypertensive patients.2. Left ventricular systolic and diastolic function and left ventricular systolic synchronicity were impaired in hypertensive patients with overweight and obesity.3. Compared to hypertensive patients without LVH, left ventricular systolic and diastolic function and synchronicity were further impaired in hypertensive patients with LVH.4. Left ventricular systolic and diastolic function and left ventricular systolic synchronicity were impaired in hypertensive patients with ventricular arrhythmia.5. Ts-max derived from TDI was a useful and sensitive index in evaluating hypertensive patients with other cardiovascular risk factors. BackgroundMS is a cluster of multiple metabolic risk factors in one individual. The component of MS is obesity, especial central obesity, diabetes and glucose intolerance, and dyslipidemia characteristic by hyperglyceridemia and low HDL-C and hypertension. In addition, MS also include tissue insulin resistance, hyperuricemia and micro-proteinuria.Patients with MS are at high risk of coronary heart disease and stroke, and cardiovascular mortality was also markedly increased in those subjects. Cardiovascular disease and all-cause mortality are increased in men with the MS, even in the absence of baseline CVD and diabetes. This means that sub-clinical cardiovascular impairments are the fundamental reasons for higher cardiovascular complications in those patients. Therefore, to finding the drug which reverses or retards cardiovascular impairments in patients with the MS is of great importance.As our knowledge of MS expanded, the role of inflammation in MS and insulin resistance becomes one attracting topic. Many studies have demonstrated that MS is a systematic low inflammation, for the levels of inflammatory mediators increased in MS. Clinical study demonstrated that inflammatory factors positive correlated with CRP, BMI, waist-hip ratio, insulin sensitivity, fasting insulin. Furthermore, the levels of CRP increased as the components of MS increase. These findings indicated that chronic subclinical inflammation is one characteristic of MS. Animal studies revealed that the expressions of interlukin-6, MCP-1 were increased in glomerulus matrix of obesity Zucker rats, and CRP, oxidant stress were significantly increased in rat model of genetic MS. These interesting findings suggest that inflammatory factors such as CRP, IL-6 may participate in the pathogenesis and development of MS.Calcium channel blockers (CCBs) are widely used to treat patients with hypertension and coronary heart disease. Clinical study demonstrated that CCBs decrease cardiovascular events in patients with coronary heart disease and intra-vascular ventricular systolic and diastolic function in hypertensive patients. Further studies revealed that CCBs decrease cardiovascular events is related to its anti-inflammation and anti-oxidant effects.Our study has proved that vascular inflammatory reaction is evident in MS, thus we hypothesized that CCBs inhibit vascular inflammation in MS and improve cardiac function in hypertensive patients.Objective1. To observe the effect of felodipine on vascular inflammation in rat model of MS and to study the possible mechanism of felodipine on vascular inflammation.2. To evaluate effect of cilnidipine on ventricular function in hypertensive patients.Methods1. Felodipine inhibits vascular inflammation in rat model of MSThirty three male Wistar rats were randomly divided into control group (n=12) and MS group (n=21). Control rats were fed with standard chow and tap water, MS rats were fed with standard chow plus high-fructose (10%, w/v) water. After high fructose feeding for 32 weeks, MS rats were further divided into two groups, MS group (n=9), continuing of high fructose feeding; felodipine group (n=9), continuing of high fructose feeding plus treatment with felodipine 5mg/kg.d by gavage. Rats of control and MS groups were given the same volume of saline by gavage. After treated for 6 weeks, all the rats were killed and the aortas were kept at -80℃.The follwing parameters were measured during the study: (1) 2 ml blood was drawn from jugular sinus of all the rats before and after fructose feeding and after treatment with felodipine for 6 weeks, serum was separated and using routine method to measuring lipid, glucose and insulin; (2) all the rats have their body weight and tail blood pressure measured once per week.At the end of the experiment, all the animal was sacrificed, the aortas were kept for the following study: (1) pathological study of aorta; (2) verhoeff elastic fibers stain; (3) real-time RT-PCR measurement of ICAM-1 and VCAM-1 mRNA; (4) immunohistochemistry for aortic ICAM-1, VCAM-1 and macrophages; (5) Western Blot for ICAM-1, VCAM-1 and IRAK-1; (6) EMSA for measuring NF-κB acticity.2. Effect cilnidipine on left ventricular function in hypertensive patientsWe selected 40 patients with mild-to-moderate hypertension and 16 normal subjects for this study. Hypertensive patients were treated with cilnidipine for 8 weeks. Before and after treatment, the participants were examined by two dimensional, M mode, pulse Doppler and tissue Doppler imaging echocardiography. Hypertensives were classified into non-left ventricular hypertrophy (NLVH) group and left ventricular hypertrophy (LVH) group. Sm, Em, Em/Am and TDI Tei index were measured to reflect left ventricular systolic and diastolic function. The control subjects were also examined by echocardiography.Results1. Felodipine inhibits vascular inflammation in rat model of MS1.1 The experimental animalsThree rats of MS group died in the entire experiment, none rat died in control group. A total of 30 rats finished the study, 12 rats in control group, 9 rats in MS group and 9 rats in felodipine group.1.2 Comparison of metabolic indexes between control and MS group after fructose feedingThere is no significant difference in terms of body weight, tail blood pressure, glucose, lipids and insulin before fructose feeding. After feeding with fructose for 32 weeks, body weight, tail blood pressure, triglyceride, insulin and HOMA were significantly increased in MS group than in control group, whereas glucose and total cholesterol showed no difference. This means the rat... |
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