| BackgroundHypercholesterolemia (HC), a fundamental risk factor of atherosclerosis (AS), is associated with impaired endothelial function[1]. Endothelial dysfunction reflected by FMD (flow-mediated dialtation) is an initiating factor and the central link of AS. Increased oxidative stress or overproduction of reactive oxygen species (ROS), which is likely to exacerbate endothelial damage and dysfunction caused by HC, were found in the patients with HC. Simultaneously endothelium dysfunction also becomes the source of ROS, which lead to promote injury in vascular function. In addition to low-density lipoprotein oxidation, reaction of ROS with cell membrane bound lipids can further a vicious cycle of continued oxidative damage, resulting in the development of atherosclerosis. It prompted us to consider improving endothelial dysfunction to reverse and delay the progression of atherosclerosis through some effective strategies.In previous studies, statins have been demonstrated to retard the progression of atherosclerosis formation and reduce both cardiovascular morbidity and mortality [2]. These beneficial effects of statins are reasonably due to its pleiotropy including improvement of endothelial function, reduction of oxidative stress and stabilization of atherosclerotic plaques[3,4].These findings have motivated our interest in investing whether pitavastatin calcium, a newly developed statin called "super statins" with a stronger reducing cholesterol effect, could reduce the oxidative stress and ameliorate the endothelial dysfunction induced by HC. Moreover, it has not yet been possible to explain the mechanisms improving endothelial function in HC patients. Thus, the present study was to determine whether endothelial dysfunction was reversed by pitavastatin and whether it is mediated by its anti-oxidant properties in HC.Objectives(1)To elucidate the changes of the endothelial function in the patients with the hypercholesterolemia;(2)To detect the variation of the oxidative stress levels (serum gp91phox and plasma 8-iso-PGF2a);(3)To assess the effect of the ptavastatin calcium on the endothelial function and oxidative stress in patients with HC;(4) To probe its possible mechanism of amelioration the endothelial function in the HC patients after pitavastatin calcium therapy.Subjects and methodsThis work was carried out at the Qilu Hospital, Shandong University. A total of forty patients with HC (hypercholesterolemia) were randomized to administration of pitavastatin calcium 1 mg or 2 mg daily for 8 weeks. Among of them,20 people were taken pitavastatin calcium lmg (5men,15women,55.20±8.35 yr of age),20 people were taken pitavastatin calcium 2mg (9men,11 women,57.56±6.09 yr of age) and thirty healthy subjects (14 men,16women,54.94±6.90 yr of age) were chosen as controls. Two people were shedding in pitavastatin calcium lmg and 2mg groups, respectively. Thus, there were 18 people in the end of follow-up period in any group (3men,5women,56.00±7.85 yr of age; 7men, llwomen,57.79±6.46yr of age). Endothelial function was evaluated by measuring the flow-mediated vasodilation (FMD) of the brachial artery. B-mode ultrasonography of the brachial artery was performed and ultrasound images were acquired using a 5～10MHz linear array transducer and a commercially available ultrasound machine (Sequia 512, Siemens).Before and 8 weeks after treatment, clinical biochemical indicators, plasma 8-iso-PGF2a and serum gp91phox (biomarkers of oxidative stress) were measured and concomitantly FMD was measured by ultrasound examination. A specific enzyme immunoassay kit (Cayman Chemical) was used to measure the 8-iso-PGF2a concentration in plasma samples. Meanwhile, enzyme linked immunoassay kit (BG) was used to measure the gp91phox concentration in serum samples.Results(1)Clinical characteristics of the control group and HC (hypercholesterolemia) group (the pre-therapy groups and post-therapy groups):Compared with the controls, the lmg pre-therapy group showed significantly higher BMI (body mass index), HC (hip circumference), MAP (mean arterial pressure) (P<0.05～0.001), the 2mg pre-therapy group showed significantly higher BMI, HC, SBP (systolic blood pressure), DBP (diastolic blood pressure), PP (pulse pressure), MAP (P<0.05～0.001). Compared with the pre-therapy group, the basic clinical characteristics did not change significantly no matter lmg or 2mg group (P>0.05). There was no significance between the post-therapy groups (P>0.05).(2) The ultrasonic characteristics of persons currently receiving pitavastatin calcium compared to the controls are shown in Table 2. Compared with the controls, persons with HC (the lmg pre-therapy group) were significantly decreased△D, FMD,△V,△V(%) (P<0.05～0.001), persons with HC (the 2mg pre-therapy group) were also significantly decreased△D, FMD,△V,△V(%) (P<0.01～0.001). After 8 weeks of pitavastatin therapy, no matter lmg or 2mg, FMD was significantly improved compared to baseline values (P<0.001). No difference in any index was noted between lmg group and 2mg group after therapy (P>0.05).(3) Compared with the controls, persons with HC (both lmg and 2mg groups) were significant higher gp91phox,8-iso-PGF2a (P<0.05-0.001); Compared with the pre-therapy groups, the levels of 8-iso-PGF2a and gp91phox were obviously decreased after therapy (P<0.05～0.001) no matter lmg or 2mg. There was also no significance between the post-therapy groups (P>0.05).(4) Compared with the controls, persons with HC (the pre-therapy groupl) were significant higher TC (total cholesterol), TG (triglyceride), LDL (low density lipoprotein cholesterol), FBG (fasting blood glucose), TP (total protein), ALB (albumin), GLB (globulin), BUN (blood urea nitrogen) (P<0.05～0.001); persons with HC (the pre-therapy group2) were significant higher TC, LDL, TG, FBG, TP, ALB, GLB, ALT, AST, Cr, r-GGT (P<0.05～0.001). Compared with the pre-therapy group, TC, LDL were obviously lowered in group 1 and group2, however, there were no significance changes in ALT, AST, Cr, CK and HDL after treatment no matter 1mg or 2mg group (P>0.05). There was also no significance between the post-therapy groups (P>0.05).(5) Multivariate linear regression model for FMD①Multivariate linear regression model for FMD is as follows:FMD=2.109×HC (hip circumference)-1.210×BMI. The HC (P=0.000) and BMI (P=0.012) were enrolled, among which the BMI was a risk factor for the endothelial function.②Multivariate linear regression model for FMD is as follows:FMD =1.420×TP-0.539×TC, the TP (P=0.000) and TC (P=0.004) were enrolled, among which the TC was a risk factor for the endothelial function.(6) Multivariate linear regression model for gp91phox①Multivariate linear regression model for gp91phox is as follows: gp91phox =0.473×Age+0.504×BMI. The age (P=0.000) and BMI (P=0.000) were enrolled, among which the age and the BMI were risk factors for the oxidative stress.②Multivariate linear regression model for gp91phox is as follows:gp91phox =0.418×Age+0.556×BMI. The age (P=0.014) and WHR (P=0.001) were enrolled, among which the age and the WHR were risk factors for the oxidative stress.③Multivariate linear regression model for gp91phox is as follows:gp91phox =0.464×LDL+0.527×FBG. The LDL (P=0.000) and FBG (P=0.000) were enrolled, among which the age and the WHR were risk factors for the oxidative stress.(7) Multivariate linear regression model for 8-iso-PGF2a①Multivariate linear regression model for 8-iso-PGF2αis as follows: 8-iso-PGF2α=0.704×WHR. The WHR (P=0.000) was enrolled, among which the WHR was a risk factor for the oxidative stress.②Multivariate linear regression model for 8-iso-PGF2αis as follows: 8-iso-PGF2α=0.699×Age. The age (P=0.000) was enrolled, among which the age was a risk factor or the oxidative stress. ③Multivariate linear regression model for 8-iso-PGF2a is as follows: 8-iso-PGF2a=0.714×LDL. The LDL (P=0.000) was enrolled, among which the LDL was a risk factor for the oxidative stress.(8) Partial correlation of FMD with lipids profile①C and TG significantly correlated negatively with FMD (r=-0.228,P=0.027 and r=-0.309, P=0.002), which denoted the FMD, even after adjusting age, BMI, SBP, DBP, FBG, smoke, drink and statin for partial correlation analysis. That is, TC and TG are independent risk factors for endothelial function in the HC patients.②TC and LDL significantly correlated negatively with FMD (r=-0.243, P=0.018 and r=-0.292, P=0.004), which denoted the FMD, even after age, WHR, SBP, DBP, FBG, smoke, drink and statin were controlled for partial correlation analysis. That is, TC and LDL are independent risk factors ffor endothelial function in the HC patients.(9) Partial correlation of gp91phox with lipids profile①C, LDL and TG significantly correlated positively with gp91phox (r=0.386, P=0.000; r=0.423, P=0.000 and r=0.271, P=0.008), which denoted the gp91phox, even after adjusting BMI, SBP, DBP, FBG, smoke and drink for partial correlation analysis. That is, TC, LDL and TG are independent risk factors for oxidative stress in the HC patients.②TC, LDL and TG significantly correlated positively with gp91phox (r=0.330, P=0.001, r=0.267, P=0.009, r=0.232, P=0.024), which denoted the gp91phox, even after age, WHR, SBP, DBP, FBG, smoke and drink were controlled for partial correlation analysis. That is, TC, LDL and TG are independent risk factors for oxidative stress in the HC patients.(10) Partial correlation of 8-iso-PGF2a with lipids profile③LDL significantly correlated positively with 8-iso-PGF2a (r=0.236, P=0.024), which denoted the 8-iso-PGF2a, even after age, BMI, SBP, DBP, FBG, smoke and drink were controlled for partial correlation analysis. That is, LDL is an independent risk factor for oxidative stress in the HC patients. ②LDL significantly correlated positively with 8-iso-PGF2a (r=0.237, P=0.024), which denoted the 8-iso-PGF2a, even after age, WHR, SBP, DBP, FBG smoke and drink were controlled for partial correlation analysis. That is, LDL is an independent risk factor for oxidative stress in the HC patients.(11)Analysis of covariance (ANCOVA) was chosen to assess the validity of pitavastatin calcium reversing endothelial dysfunction and decreasing oxidative stress.FMD (P=0.022) was significantly higher, gp91phox (P=0.046) and 8-iso-PGF2a (P=0.008) were significantly lower, even after lipids were controlled for analysis of covariance (ANCOVA). It suggested that high cholesterol levels were closely related with endothelial dysfunction and enhanced oxidative stress in HC patients. It also suggested that pitavastatin calcium can indeed ameliorate the endothelial dysfunction and lower enhanced oxidative stress HC patients.Conclusions(1) Endothelial function assessed by FMD was impaired in patients with hypercholesterolemia;(2)Indexes of the oxidative stress (plasma 8-iso-prostaglandin F2a and serum gp91phox) were significantly increased in the hypercholesterolemia;(3)The levels of oxidative stress were significantly reduced and endothelial function obviously improved by pitavastatin calcium treatment in patients with hypercholesterolemia;(4)Pitavastatin calcium ameliorates the endothelial dysfunction of the patients with hypercholesterolemia by antioxidant stress mechanism. ObjectiveTo investigate whether endothelial function can be improved by the treatment of pitavastatin calcium via its antioxidant properties in hypercholesteremia patients.MethodsForty patients with hypercholesteremia were randomized to receive pitavastatin calcium lmg/d or 2mg/d for 8 weeks. Among them, four people were lost in the follow-up period. Before and after treatment, clinical and biochemical characteristics, markers of oxidative stress (plasma 8-iso-prostaglandin F2αand serum gp91phox) were determined and concomitantly endothelium-dependent brachial artery flow-mediated dilation (FMD) was measured by ultrasound examination. Thirty healthy subjects were chosen as controls.RESULTSFor individuals with hypercholesteremia, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), serum gp91phox were significantly increased (P<0.001 for all), plasma 8-iso-prostaglandinF2a (8-iso-PGF2a) was significantly higher (P<0.05), while FMD was obviously impaired (P<0.001). TC, LDL-C and serum gp91phox were significantly reduced (P<0.001 for all), plasma 8-iso-PGF2a was lower and FMD was significantly improved after pitavastatin calcium treatment as compared with those before treatment in any group (P<0.05 for both). However, there was no significant difference between the lmg and 2mg pitavastatin calcium groups post-therapy. CONCLUSIONSEndothelial dysfunction induced by hypercholesteremia can be ameliorated by pitavastatin calcium treatment, which in part through its anti-oxidative properties.IntroductionAtherosclerosis is pathological physiological mechanism of cardiovascular disease. Hypercholesterolemia(HC), a fundamental risk factor of atherosclerosis(AS), is associated with impaired endothelial function[1] and that it is endothelial dysfunction, which is reflected by FMD, that is an initiating factor and the central link of AS. Reactive oxygen (ROS) is proposed to contribute to the origin and development of cardiovascular diseases[2].Increased oxidative stress or overproduction of ROS, which is likely to exacerbate endothelial damage and dysfunction caused by HC, were found in the patients with HC. NADPH oxidase, one of the most important cellular producers of ROS [3], gp91phox is a key subunit.8-iso-prostaglandin F2α(8-iso-PGF2a), a lipid peroxidation biomarker) is one of the most reliable indices for assessing oxidative stress status[4]. To estimate the oxidative stress status, gp91phox and 8-iso-PGF2a were used. Simultaneously dysfunction endothelium also becomes the source of ROS, which lead to promote injury in vascular function. In addition to low-density lipoprotein oxidation, reaction of ROS with cell membrane bound lipids can further a vicious cycle of continued oxidative damage, resulting in the development of atherosclerosis. It prompted us to consider improving endothelial dysfunction to reverse and delay the progression of atherosclerosis through some effective strategies.In previous studies, statins have been demonstrated to retard the progression of atherosclerosis formation and reduce both cardiovascular morbidity and mortality[5]. These beneficial effects of statins are reasonably due to its pleiotropy involving reduction of oxidative stress, improvement of endothelial function and stabilization of atherosclerotic plaques[6,7].Growing number of researchers are focusing on statins to improve endothelial function in anti-atherosclerosis filed. The detailed mechanisms... |
PDF Full Text Request