Peroxisome proliferator-activated receptor gamma inhibits hepatic fibrosis in rats

BACKGROUND:Hepatic fibrosis is a necessary step in the development of hepatic cirrhosis.In this study we used lentiviral vector-mediated transfection technology to evaluate the effect of peroxisome proliferator-activated receptor gamma(PPAR-γ) on rat hepatic fibrosis. METHODS:Hepatic fibrosis in rats was induced by CCl4 for 2 weeks(early fibrosis)and 8 weeks(sustained fibrosis).The rats were randomly divided into four groups:normal control, fibrosis,blank vector,and PPAR-γ.They were infected with the recomb...     

Electrophysiologic consequences of chronic experimentally induced left ventricular pressure overload

Cardiac electrophysiologic alterations were evaluated 1 to 8 months after partial supracoronary aortic constriction in cats. This procedure induced left ventricular systolic hypertension and hypertrophy with marked connective tissue infiltration. In situ, premature ventricular complexes were observed during or after vagal slowing of sinus rate in 8 (26%) of the 31 experimental animals, while an additional 3 of the 31 developed ventricular fibrillation. No arrhythmias were recorded in 31 normal or 7 sham-operated cats. In vitro, 29% of the left ventricular preparations from cats with pressure overload and 5% from control cats showed spontaneous ectopic activity. During stimulation at cycle lengths of 800 to 1,000 ms, multiple site impalements of subendocardial muscle cells within fibrotic regions revealed heterogeneous electrical abnormalities. These included short action potential duration, low amplitude action potentials generated from low resting potentials, split upstrokes and electrically silent areas. Impalements in nonfibrotic areas of the left ventricle showed prolongation of muscle action potential duration. Long-term disturbances in cellular electrophysiologic properties may favor the development of arrhythmias and thereby contribute to sudden cardiac death in left ventricular hypertension and hypertrophy.     

过氧化物酶体增殖物激活受体γ激动剂对直流电刺激后兔缺血心肌组织中PTEN蛋白表达及左室重构的影响

目的探讨染色体10缺失的磷酸酶与张力蛋白同源物基因（PTEN）在兔急性心肌梗死（MI）边缘区心肌组织中的表达及其意义以及过氧化物酶体增殖物激活受体（PPAR）γ激动剂（罗格列酮）对其表达的影响。方法50只日本大耳白兔,随机分为假手术组（SH组,n=5）、MI组n=15、常规电刺激组（EFs组,n=15）和罗格列酮干预电刺激组（R．EFs组,n=15）。结扎冠状动脉左前降支建立急性MI或SH组模型后,在结扎血管两侧心外膜上缝合固定一对铂金电极,直流电刺激（电场强度4．0V／cm,30min／d）,罗格列酮以4mg／（kg·d）灌胃。实验终点以Western印迹法检测各组1周、2周及4周时心肌组织中PTEN表达并测定左、右心室重量和血流动力学指标。结果正常心肌组织和缺血心肌组织均有一定程度PTEN表达,EFs组心肌组织中PTEN表达较MI组升高（P〈0．01）,罗格列酮干预使缺血心肌组织中PTEN表达较EFs组进一步升高（P〈0．05）,同时左室收缩功能较EFs组进一步改善。结论PPARy激动剂可进一步促进缺血心肌组织在直流电刺激后PTEN的表达,从而使左心室功能得到改善。     

Sex-dependent differences in left ventricular function and structure in chronic pressure overload

To evaluate gender-related differences in left ventricular (LV)structure and function in aortic stenosis, LV biplane cineangiography,micromanometry and endomyocardial biopsies were carried outin 56 patients with aortic stenosis and normal coronary arteries.Patients were divided into males (M: n=35), and females (F:n=21). Sixteen normal subjects 8 M, 8 F) served as haemodynamiccontrols. Control biopsy data were obtained from six pre-transplantationdonor hearts (3 M and 3 F). LV systolic function was evaluatedby ejection fraction and its relationship to mean systolic circumferentialwall stress, diastolic function by the time constant of LV pressuredecay, peak filling rates and passive myocardial stiffness constant.Biopsy samples were evaluated for interstitial fibrosis, musclefibre diameter and volume fraction of myofibrils. In a subsetof 27 consecutive patients, biopsy samples were evaluated witha morphometric-morphological method, for total collagen volumefraction, endocardial fibrosis and the extension and thicknessof orthogonal collagen fibres (cross-hatching). In patients with aortic stenosis, aortic valve area, aorticvalve resistance and mean aortic pressure gradient were comparablein males and females, whereas end-systolic and end-diastolicvolumes were larger in males than females. Ejection fractionwas lower (56%) in males than females (64%) (P<0.05); 20of 35 males and four of 21 females had depressed systolic contractilitywhen assessed with regard to the relationship ejection fraction-meansystolic stress (P<0.01). Myocardial stiffness constant washigher in males than in females (P<0.0I). Nine of 14 malesand two of 13 females had endocardial fibrosis (P<0.009),whereas increased cross-hatching (> 1.5 grade) was presentin 11 males and four females with aortic stenosis (P<0.0I).An abnormal collagen architecture was present in 13114 malesand 5113 females (V<0.002). In aortic stenosis, males have a depressed systolic functionand abnormal passive elastic properties when compared to femaleswith valve lesions of similar severity. Changes in collagenarchitecture may account, at least in part, for these differences.     

Early improvement in left ventricular diastolic function after relief of chronic right ventricular pressure overload

Chronic right ventricular pressure overload is associated with left ventricular diastolic dysfunction. Whether or not an abrupt reduction in pulmonary artery pressure in patients with chronic pulmonary hypertension results in early improvement of left ventricular diastolic function is unknown. To assess this, the Doppler indexes of left ventricular diastolic function and echocardiographic measures of left ventricular volume were analyzed in 22 patients (age, 41 +/- 14 years, mean +/- SD) before and within 1 week after pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension. Mean duration of cardiopulmonary symptoms was 37 months (range, 4 months to 9 years). After operation, mean pulmonary artery pressure and pulmonary vascular resistance decreased (50 +/- 13 to 29 +/- 9 mm Hg and 904 +/- 654 to 283 +/- 243 dynes.sec/cm5, respectively, both p less than 0.001), pulmonary artery wedge pressure was unchanged (11 +/- 5 to 12 +/- 5 mm Hg), and cardiac index increased (2.0 +/- 0.5 to 2.8 +/- 0.7 l/min/m2 p less than 0.001). Left ventricular end-diastolic volume and stroke volume increased significantly (58.5 +/- 18.0 to 76.6 +/- 25.0 ml and 30.3 +/- 12.3 to 41.8 +/- 12.5 ml, respectively, both p less than 0.001) after surgery.(ABSTRACT TRUNCATED AT 250 WORDS)     

Peroxisome proliferator-activated receptor gamma in human breast carcinoma: a modulator of estrogenic actions

It has been reported that agonists of peroxisome proliferator-activated receptor gamma (PPARgamma) inhibit proliferation of breast carcinoma cells, but the biological significance of PPARgamma remains undetermined in human breast carcinomas. Therefore, we immunolocalized PPARgamma in 238 human breast carcinoma tissues. PPARgamma immunoreactivity was detected in 42% of carcinomas, and was significantly associated with the status of estrogen receptor (ER) alpha, ERbeta, progesterone receptor, retinoic X receptors, p21 or p27, and negatively correlated with histological grade or cyclooxygenase-2 status. PPARgamma immunoreactivity was significantly associated with an improved clinical outcome of breast carcinoma patients by univariate analysis, and multivariate analysis demonstrated that PPARgamma immunoreactivity was an independent prognostic factor for overall survival in ERalpha-positive patients. We then examined possible mechanisms of modulation by PPARgamma on estrogenic actions in MCF-7 breast carcinoma cells. A PPARgamma activator, 15-deoxy-Delta(12,14)- prostaglandin J(2) (15d-PGJ(2)), significantly inhibited estrogen-responsive element-dependent transactivation by estradiol in MCF-7 cells, which was blocked by addition of a PPARgamma antagonist GW9662. Subsequent study, employing a custom-made microarray focused on estrogen-responsive genes, revealed that mRNA expression was significantly regulated by estradiol in 49 genes, but this significance vanished on addition of 15d-PGJ(2) in 16 out of 49 (33%) genes. These findings were confirmed by real-time PCR in 11 genes. 15d-PGJ(2) significantly inhibited estrogen-mediated proliferation of MCF-7 cells, and caused accumulation of p21 and p27 protein. These results suggest that PPARgamma is mainly expressed in well-differentiated and ER-positive breast carcinomas, and modulates estrogenic actions.     

不同肾上腺素能受体阻滞剂对改善压力负荷大鼠左室重塑的作用

目的　比较卡维地洛、美托洛尔和特拉唑嗪对压力超负荷性左室心肌胶原结合蛋白(collagen bindingprotein ,Colligin)和肌球蛋白同工酶 (α/ β MHC)表达的影响 ,探讨卡维地洛改善左室重塑的新机制。方法　将腹主动脉缩窄术后 4周的雄性Wistar大鼠随机分为腹主动脉缩窄术、卡维地洛、美托洛尔、特拉唑嗪 4组 (n =8)。治疗 12周后 ,观察各组大鼠各项指标的变化。结果　术后 16周大鼠左室明显肥厚 ,α/ β MHCmRNA的比值下降 ,ColliginmRNA表达及Ⅰ /Ⅲ型胶原和Colligin蛋白含量增加 (P <0 0 5 ) ;药物治疗 12周后 ,卡维地洛能够明显改善左室肥厚 ,美托洛尔次之 ,而特拉唑嗪作用不明显 ;卡维地洛组大鼠左室心肌Ⅰ /Ⅲ型胶原和Colligin蛋白的表达下降 ,α/ β MHCmRNA表达比值增加 ,ColliginmRNA表达下调 (P <0 0 5 ) ,但美托洛尔组和特拉唑嗪组无此变化 (P >0 0 5 )。结论　卡维地洛与美托洛尔均能明显改善左室肥厚 ,而非选择性 β肾上腺素能受体阻滞剂卡维地洛更能下调心室细胞外基质蛋白和逆转肌球蛋白同工酶转换 ,其作用机制有待进一步确定。     

过氧化物酶体增殖剂活化受体α信号通路对肥厚心肌能量代谢胚胎型再演的调控作用

目的 研究压力负荷性大鼠左室肥厚心肌中链脂酰辅酶A(MCAD)、肌型肉碱棕榈酰转移酶(M—CPT-I)和过氧化物酶体增殖剂活化受体α(PPARα)基因／蛋白的表达变化，阐明肥厚心肌能量代谢“胚胎型再演”的分子机制和PPARα的调控作用。方法取健康雄性Wistar大鼠行腹主动脉缩窄(CAA)制成左室肥厚模型，随机分为2周组(CAA2w组)、4周组(CAA4w组)、8周组(CAA8w组)、16周组(CAA16组)，设立假手术组作为对照，以上每组均为12只，观察各组大鼠各项指标的变化。结果(1)与假手术组比较，CAA各组大鼠左心室湿重／体重、平均动脉压升高，4周后左室舒张末压、左室收缩压、 dp／dtmax开始升高，术后8周-dp／dtmax开始降低，以CAA16w组最显著，而CAA各组右心室湿重／体重无明显变化；(2)CAA各组大鼠血清和心肌游离脂肪酸含量进行性增加；(3)CAA各组大鼠左室心肌M—CPT-I、MCADmRNA的表达逐渐下降；(4)CAA各组大鼠左室心肌PPARα基因表达下调，术后8周PPARα蛋白水平开始下调，以CAA16w组最显著。结论(1)在腹主动脉缩窄所致的肥厚心肌模型中，血清和心肌游离脂肪酸含量增加，表明脂肪酸的利用减少，心肌能量代谢呈“胚胎型再演”，调控脂肪酸氧化关键酶(M—CPT-I和MCAD)的基因表达下调，可能是导致“胚胎型再演”的分子基础；(2)核转录因子PPARα活性下调，与肥厚心肌编码线粒体脂肪酸氧化酶核基因的表达和脂肪酸的利用下调相一致，提示PPARα信号对压力负荷肥厚心肌的能量代谢具有重要的调控作用。     

Concentric left ventricular remodeling in endothelial nitric oxide synthase knockout mice by chronic pressure overload

OBJECTIVE: Heart failure as a consequence of sustained hemodynamic overload is among the most prevalent diseases in developed countries. The aim of the present study was to investigate the specific role of endothelial nitric oxide synthase (eNOS) in pressure overload-induced left ventricular (LV) hypertrophy. METHODS AND RESULTS: Chronic pressure-overload LV hypertrophy was induced by abdominal aortic banding (AC) in wild-type (WT) and eNOS(-/-) mice. Six weeks after abdominal AC, the consequences of the sustained pressure overload on LV morphology and function were noninvasively and invasively assessed using echocardiography and a 1.4 F conductance catheter. Sham-operated eNOS(-/-) mice had significantly increased systolic blood pressure, slightly enhanced systolic function (preload recruitable stroke work) and normal diastolic function but no evidence of left ventricular hypertrophy when compared to sham-operated WT animals. AC resulted in a greater increase in anterior wall thickness in eNOS(-/-) mice (0.8+/-0.03 mm) compared to WT mice (0.7+/-0.03 mm; P<0.05). The LV end-diastolic diameter was unchanged by AC in eNOS(-/-) mice (sham: 3.8+/-0.1 mm, AC: 3.7+/-0.2 mm) but significantly increased in WT mice (sham: 3.9+/-0.1 mm, AC: 4.5+/-0.2 mm; P<0.05). Interstitial fibrosis and myocyte hypertrophy were greater in eNOS(-/-) than in WT mice after AC. AC in eNOS(-/-) mice caused a greater diastolic than systolic dysfunction compared to WT mice. CONCLUSION: Chronic pressure overload in eNOS(-/-) mice results in concentric LV hypertrophy without LV dilation and impaired systolic and diastolic function. These findings suggest that eNOS limits LV remodeling and dysfunction and modulates extracellular matrix proteins under chronic pressure overload.     

Cardiocyte cytoskeleton in patients with left ventricular pressure overload hypertrophy

OBJECTIVES: We sought to determine whether the cardiocyte microtubule network densification characteristic of animal models of severe pressure overload cardiac hypertrophy occurs in human patients. BACKGROUND: In animal models of clinical entities causative of severe right and left ventricular (LV) pressure overload hypertrophy, increased density of the cellular microtubule network, through viscous loading of active myofilaments, causes contractile dysfunction that is normalized by microtubule depolymerization. These linked contractile and cytoskeletal abnormalities, based on augmented tubulin synthesis and microtubule stability, progress during the transition to heart failure. METHODS: Thirteen patients with symptomatic aortic stenosis (AS) (aortic valve area = 0.6 +/- 0.1 cm2) and two control patients without AS were studied. No patient had aortic insufficiency, significant coronary artery disease or abnormal segmental LV wall motion. Left ventricular function was assessed by echocardiography and cardiac catheterization before aortic valve replacement. Left ventricular biopsies obtained at surgery before cardioplegia were separated into free and polymerized tubulin fractions before analysis. Midwall LV fractional shortening versus mean LV wall stress in the AS patients was compared with that in 84 normal patients. RESULTS: Four AS patients had normal LV function and microtubule protein concentration; six had decreased LV function and increased microtubule protein concentration, and three had borderline LV function and microtubule protein concentration, such that there was an inverse relationship of midwall LV fractional shortening to microtubule protein. CONCLUSIONS: In patients, as in animal models of severe LV pressure overload hypertrophy, myocardial dysfunction is associated with increased microtubules, suggesting that this may be one mechanism contributing to the development of congestive heart failure in patients with AS.     

Correlation of left ventricular diastolic filling characteristics with right ventricular overload and pulmonary artery pressure in chronic thromboembolic pulmonary hypertension

OBJECTIVES: This study was designed to determine a quantitative relationship between right ventricular (RV) pressure overload and left ventricular (LV) diastolic filling characteristics in patients with chronic thromboembolic pulmonary hypertension (CTEPH). BACKGROUND: Right ventricular pressure overload in patients with CTEPH causes abnormal LV diastolic filling. However, a quantitative relationship between RV pressure overload and LV diastolic function has not been established. METHODS: We analyzed pre- and postoperative diastolic mitral inflow velocities and right heart hemodynamic data in 39 consecutive patients with CTEPH over the age of 30 (55 +/- 11 years) with mean pulmonary artery pressure >30 mm Hg who underwent pulmonary thromboendarterectomy (PTE). RESULTS: After PTE, mean pulmonary artery pressure (mPAP) decreased from 50 +/- 11 to 28 +/- 9 mm Hg (p < 0.001) while cardiac output (CO) increased from 4.4 +/- 1.1 to 5.7 +/- 0.9 l/m (p < 0.001). Mitral E/A ratio (E/A) increased from 0.74 +/- 0.22 to 1.48 +/- 0.69 (p < 0.001). E/A was < 1.25 in all patients pre-PTE. After PTE, all patients with E/A >1.50 had mPAP <35 mm Hg and CO >5.0 l/min. E/A correlated inversely with mPAP (r = 0.55, p < 0.001) and directly with CO (r = 0.53, p < 0.001). CONCLUSIONS: E/A is consistently abnormal in patients with CTEPH and increases post-PTE. Moreover, E/A varies inversely with mPAP and directly with CO. Following PTE, E/A >1.5 correlates with the absence of severe pulmonary hypertension (mPAP >35 mm Hg) and the presence of normal cardiac output (> 5.0 l/m).     

Regional left ventricular wall motion abnormalities in chronic volume overload

Computer-assisted analysis of left ventricular (LV) wall motion has been performed in 12 patients (pts) with chronic volume overload and in seven normal subjects. All pts were in sinus rhythm, without congestive heart failure and without coronary artery disease at selective coronary angiography; 30 degrees right anterior oblique ventriculograms were employed in each case. Thirty-six radiants were automatically traced and the percent shortening of each radiant was calculated using two different reference methods (fix and floating methods). In valvular heart disease (VHD) pts LV volumes were significantly increased, and ejection fraction and LV eccentricity were significantly reduced. LV eccentricity inversely correlated with LV volumes. VHD pts showed regional LV abnormalities. Inferoapical and anterior wall motion was significantly reduced (two-sample t-test P less than 0.05) using the fix method. With this method a significant inverse correlation between percent shortening of the radiants correspondent to the inferoapical region and end-diastolic and end-systolic volumes was found; a significant direct correlation was found with LV systolic eccentricity. Ejection fraction directly correlated with the percent shortening of radiants correspondent to both the anterior and inferior regions. The role of LV "dynamic geometry" alterations as a possible cause for the observed regional LV wall motion abnormalities is emphasized.     

压力超负荷兔左心室结构和功能的动态改变及其意义

目的探讨慢性压力超负荷兔左心室结构和功能的动态改变及其意义。方法采用肾上腹主动脉缩窄方法制备兔左心室短期压力超负荷模型,设立假手术组,术后2周和8周通过心导管法测定左心室功能;采用胶原酶两步消化法分离获取左心室中层单个心肌细胞,应用激光扫描共聚焦显微镜技术测定中层细胞体积和蛋白含量,全细胞膜片钳技术测定中层细胞膜电容。结果术后2周和8周,缩窄组主动脉收缩压、舒张压、左室收缩压均较假手术组显著升高（P〈0．05或P〈0．01）;术后2周,与假手术组比较,缩窄组左室压力最大上升和下降速率（＋dp／dtmax）、左室舒张末压（LVEDP）、左室收缩指数、T值（左室松弛时间常数）无明显改变,左室中层细胞体积、蛋白含量及膜电容差异亦无统计学意义;术后8周,与假手术组比较,缩窄组＋dp／dtmax、左室收缩指数及LVEDV无明显改变,LVEDP[（3．35±1．51）mmHg和（6．89±2．01）mmHg,P〈0．01]和T值[（11．98±3．70）ms和（22．17±6．64）ms,P〈0．01]明显升高,中层细胞体积[（26689．41±2107．21）μm^3和（34165．87±3245．03）μm^3,P〈0．05]、蛋白含量[（104．73±4．45）×10^4荧光强度和（144．86±5．62）×10^4荧光强度,P〈0．01]及膜电容[（116．57±6．94）pF比（156．21±11．20）pF,P〈0．05]显著增加。结论慢性压力超负荷2周,兔左心室收缩功能正常,无心肌细胞肥大。     

Peroxisome proliferator-activated receptor activation increases imatinib uptake and killing of chronic myeloid leukemia cells

Low pretreatment expression of the imatinib uptake transporter human organic cation transporter 1 (hOCT1) is associated with inferior complete cytogenetic response rates, progression-free survival, and overall survival in imatinib-treated chronic myeloid leukemia (CML). Upregulation of hOCT1 can therefore increase the uptake of imatinib. The hOCT1 gene is transactivated by hepatocyte nuclear factor 4α in human liver, and peroxisome proliferator-activated receptors (PPAR) α and γ activation increases OCT1 expression in mouse hepatocytes. Here we report that no isoform of hepatocyte nuclear factor 4α is expressed in CML lines or in CML primary cells. In contrast, both PPARα and γ were expressed in all CML cell lines and primary cells studied. PPARα agonist treatment increased imatinib killing of CML KCL22 cells and primitive CD34(+) cells, and also upregulates hOCT1 gene expression and increases imatinib uptake into KCL22 cells and primary cells. PPARα agonists might potentially be of clinical use in CML patients failing imatinib.