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ABSTRACT: AIMS: Oxidative stress is implicated in the pathology of pulmonary arterial hypertension. Previously, we demonstrated that vardenafil, a phosphodiesterase-5 inhibitor, has potential as therapy for pulmonary arterial hypertension, although the mechanism remained uncharacterized. Here, we aimed to determine baseline levels of oxidative stress in pulmonary arterial hypertension and investigate whether vardenafil affects oxidative stress levels while improving pulmonary arterial hypertension.Methods and ResultsSprague-Dawley rats with monocrotaline-induced pulmonary arterial hypertension were administered oral vardenafil 1 mg kg(-1) day(-1) for 21 days (n=12). Treatment-naïve patients (n=15) with PAH were treated with vardenafil 5 mg twice daily for 3 months. Haemodynamic data and plasma levels of nitrate/nitrite and products of oxidative damage were determined in rats and patients. Histopathology, immunohistochemistry and assessments of oxidative/anti-oxidative enzyme expression were performed in rat lung tissue. Compared with baseline (patients) or untreated controls (rats) vardenafil significantly reduced pulmonary vascular resistance and increased cardiac output. In rats, vardenafil suppressed proliferation and enhanced apoptosis of pulmonary artery smooth muscle cells, attenuating small pulmonary artery remodelling and right ventricular hypertrophy. Vardenafil significantly reduced levels of oxidative stress biomarkers, such as 8-iso-prostaglandin-F2α and 3-nitrotyrosine, and significantly increased nitric oxide levels in rats and patients. Furthermore, vardenafil significantly increased endothelial nitric oxide synthase expression and superoxide dismutase activity, and down-regulated nicotinamide adenine dinucleotide phosphate oxidase expression in rat lung tissue. CONCLUSIONS: Vardenafil reduces oxidative stress in rats and humans while improving pulmonary arterial hypertension, warranting investigation of oxidative stress pathways as targets for pulmonary arterial hypertension therapy.
Cardiovascular research 05/2013; · 5.80 Impact Factor
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Wen-Hui Wu,
Lu Yang,
Fu-Hua Peng,
Jing Yao,
Li-Ling Zou, Dong Liu,
Xin Jiang,
Jue Li,
Lan Gao,
Jie-Ming Qu,
Steven M Kawut,
Zhi-Cheng Jing
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ABSTRACT: RATIONALE: Lower socioeconomic status (SES) confers a heightened risk of common cardiovascular and pulmonary diseases and increased mortality. The association of SES with outcomes in patients with pulmonary arterial hypertension (PAH) is less clear. OBJECTIVES: To determine the association between SES and outcomes in PAH patients. METHODS: We performed a prospective cohort study at a national referral center for PAH patients in China. Two hundred and sixty-two consecutive incident patients aged 18 to 65 years with a diagnosis of idiopathic PAH were recruited between January 2007 and June 2011 and followed-up until November 2011. The primary endpoint was all-cause mortality. A SES score for each patient was derived from their educational level, annual household income, occupation, and medical reimbursement rate. MEASUREMENTS AND MAIN RESULTS: Patients with a lower SES had higher unadjusted mortality rates with 3-year survival estimates of 50.1%, 70.8%, and 86.0% in increasing tertiles of SES (P for trend <0.001). After adjustment for clinical features, hemodynamics, and type of PAH treatment, the hazard ratios for death were 2.98 (95% confidence interval [CI], 1.51 to 5.89) in the lowest tertile of SES, and 1.80 (95% CI, 0.89 to 3.63) in the middle tertile of SES compared with the upper tertile (P for trend = 0.006). CONCLUSIONS: A lower SES is strongly associated with a higher risk of death in idiopathic PAH. This association was independent of clinical characteristics, hemodynamics, and treatment. Addressing the health disparities associated with a lower SES may improve the outcomes of patients with PAH.
American Journal of Respiratory and Critical Care Medicine 12/2012; · 11.08 Impact Factor
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ABSTRACT: Pulmonary hypertension (PH) continues to be a serious clinical problem with high mortality. As oestrogen is a potential vasodilator of the pulmonary circulation, this study examined the mechanisms by which 17β-oestradiol improves monocrotaline (MCT)-induced PH.Female Sprague-Dawley rats underwent bilateral ovariectomy or sham operations. The rats received MCT (50 mg·kg(-1)) and were treated with 17β-oestradiol (1 mg·kg(-1)·day(-1)) for 5 weeks or only from Week 4 to Week 5. Plasma 17β-oestradiol concentrations were decreased in sham-operated, MCT-treated rats compared with sham-operated rats (17.7±4.7 vs 50.3±15.4 pg·mL(-1); p=0.029). The 17β-oestradiol anabolic enzyme cytochrome P450 (CYP) 19 was decreased by MCT treatment, while the catabolic enzymes CYP 1A1 and 1B1 were increased. Ovariectomized and MCT-treated rats had more severe PH. 17β-oestradiol suppressed pulmonary arterial smooth muscle cell proliferation and macrophage infiltration, and enhanced apoptosis by increasing nitric oxide and prostacyclin levels and reducing endothelin-1 levels. PI3K and Akt phosphorylations were markedly increased but were inhibited by 17β-oestradiol treatment in PH rats.Oestrogen deficiency may aggravate development of PH. 17β-oestradiol improved PH via activation of the PI3K/Akt pathway to regulate nitric oxide, prostacyclin and endothelin-1 expression.
European Respiratory Journal 08/2012; · 5.89 Impact Factor
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ABSTRACT: Background- BMPR2 mutations predispose to idiopathic and heritable pulmonary arterial hypertension (IPAH and HPAH). The influence of BMPR2 mutations on clinical outcome is not concordant in different ethnic groups. Although the BMPR2 mutation spectrum and mutation rate in Chinese PAH patients has been reported previously, the influence of genotype on phenotype and whether this influence is associated with sex have not been investigated. Methods and Results- We analyzed data from 305 PAH patients considered as either idiopathic or heritable who underwent genetic counseling in Shanghai Pulmonary Hospital. The clinical, functional, and hemodynamic characteristics of BMPR2 mutation carriers and noncarriers were compared. The more severe hemodynamic compromise at diagnosis in BMPR2 mutation carriers versus noncarriers is concordant with other ethnic groups. In the Chinese PAH cohort, BMPR2 mutations were associated with a higher risk of mortality after adjustment for age and sex (hazard ratio, 1.971; 95% confidence interval, 1.121-3.466; P=0.018). The overall survival difference between mutation carriers and noncarriers was more obvious in male patients, which was reflected by a higher mortality risk of male mutation carriers than that of male noncarriers after adjustment for age at diagnosis (hazard ratio, 3.702; 95% confidence interval, 1.416-9.679; P=0.008). In females, this trend did not reach statistical significance. Conclusions- BMPR2 mutations influence phenotype more obviously in male PAH patients. The pathogenesis of female PAH patients is more complicated, and the influence of BMPR2 mutations may be modified by other unknown factors, making disparities in the prognosis between female mutation carriers and noncarriers less evident.
Circulation Cardiovascular Genetics 08/2012; 5(5):511-8. · 6.11 Impact Factor
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ABSTRACT: To establish an easy and repeatable method for determination of pulmonary vascular resistance in normal and pulmonary arterial hypertension (PAH) rats.
Forty-five Sprague-Dawley rats were randomly assigned into three groups: control group, low dose monocrotaline (MCT) group (50 mg/kg) and high dose MCT group (60 mg/kg). Rats in PAH groups received single subcutaneous injection of MCT. We measured pulmonary artery pressure by right heart catheterization using an improved hand-made PE-50 catheter. Cardiac output was calculated through thermodilution method. Pulmonary vascular resistance equals the mean pulmonary artery pressure divided by cardiac output.
The total percentages of success to detect pulmonary artery pressure, cardiac output and pulmonary vascular resistance were 98%, 100% and 96% respectively in 3 groups. Twenty-one days after MCT injection, mean pulmonary artery pressure significantly increased in MCT group compared to control group [(43.1 ± 0.8), (54.8 ± 2.2) vs. (17.4 ± 1.0) mm Hg (1 mm Hg = 0.133 kPa), P < 0.001], and the mPAP was also significantly higher in high dose MCT group than in low dose MCT group (P < 0.001). Cardiac output was significantly lower in PAH rats than in control rats [(77.5 ± 6.9), (71.0 ± 6.7) vs. (126.8 ± 3.9) ml/min, P < 0.001]. Pulmonary vascular resistance was significantly increased in PAH rats compared with control rats [(0.56 ± 0.06), (0.76 ± 0.08) vs. (0.13 ± 0.01) mm Hg×min(-1)×ml(-1), P < 0.001]. There were significant differences in both MCT-treated groups (P = 0.01).
Pulmonary vascular resistance in rats could be reliably detected using the improved hand-made PE-50 right heart catheter.
Zhonghua xin xue guan bing za zhi [Chinese journal of cardiovascular diseases] 10/2011; 39(10):901-4.
