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01.12.2015 | Research article | Ausgabe 1/2015 Open Access

Oxidative stress and nitric oxide signaling related biomarkers in patients with pulmonary hypertension: a case control study

Zeitschrift:: BMC Pulmonary Medicine > Ausgabe 1/2015

Autoren:: Shuai Zhang, Ting Yang, Xiaomao Xu, Meng Wang, Linye Zhong, Yuanhua Yang, Zhenguo Zhai, Fei Xiao, Chen Wang

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Wichtige Hinweise

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

SZ and CW had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. SZ: contributed to the study design, data acquisition and collection; sample collection and biomarkers measurement; data analysis and interpretation, and manuscript preparation and revision. TY and XX: contributed to the study design; data analysis and interpretation; and manuscript preparation, revision, and approval of the final version. MW: contributed to the method establishment and evaluation; biomarkers measurement; and manuscript preparation, revision, and approval of the final version. LZ: contributed to the method establishment and evaluation; data acquisition and collection; sample collection and biomarkers measurement; and data analysis, and approval of the final version. YY: contributed to the study design; patients enrollment and assessment; data interpretation; and manuscript preparation, revision, and approval of the final version. ZZ: contributed to the study design; patients enrollment and assessment; data interpretation; and manuscript preparation, revision, and approval of the final version. FX: contributed to the study design; data analysis and interpretation; and manuscript preparation, revision, and approval of the final version. CW: contributed to the study design; data interpretation; and manuscript preparation, revision, and approval of the final version. All authors read and approved the final manuscript.

Abbreviations

Oxidative stress

Nitric oxide

Pulmonary hypertension

PAH

Pulmonary arterial hypertension

CTEPH

Chronic thromboembolic pulmonary hypertension

mPAP

Mean pulmonary artery pressure

PVRI

Pulmonary vascular resistance index

d-ROMs

Derivative of reactive oxygen molecules

BAP

Biological antioxidant potential

SOD

Superoxide dismutase

MDA

Malondialdehyde

ADMA

Asymmetric dimethylarginine

WHO

World Health Organization

Oxidative stress

ROS

Reactive oxygen species

RNS

Reactive nitrogen species

IPAH

Idiopathic pulmonary arterial hypertension

6MWD

Six minute walk distance

TBHP

Tert butyl hydroperoxide

VitC

Vitamin C

PASP

Pulmonary artery systolic pressure

Background

Pulmonary hypertension (PH) is a complex pulmonary vascular disease caused by different reasons, such as chronic hypoxia, left heart diseases, chronic respiratory diseases and thromboembolism [ 1]. In the classification of PH by World Health Organization (WHO), pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) share the pathological characteristic of vascular remodeling. Pulmonary vascular remodeling is characterized by medial hypertrophy, intimal proliferative and fibrotic changes, adventitial thickening, and thrombotic lesions [ 1]. Although the mechanisms involved are incompletely understood, endothelial dysfunction with proliferation of endothelial cells and smooth muscle cells plays an important role in vascular remodeling [ 2]. One character of endothelial dysfunction is oxidative stress (OS) [ 3, 4], which can increase the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and decrease the bioavailable nitric oxide (NO).

All vascular cells, including endothelial cells, smooth muscle cells, and adventitial cells, can produce ROS. In patients with vascular diseases, the oxidative-antioxidative balance in the vessel wall is compromised due to the increase of ROS production by these cells, sometimes coupled with decreased antioxidant defense. ROS may trigger signals that further exacerbate smooth muscle hypercontractility, endothelial barrier dysfunction, and vascular remodeling [ 5], Increasing evidence demonstrates that OS plays a contributory role in the pathogenesis of PAH [ 6- 9]. Recently, increased markers of OS have been found in various animal models, such as C57/BL6 mice exposed to hypobaric hypoxic conditions and Sprague-Dawley rats with monocrotaline-induced PAH [ 10, 11]. However, few studies have explored the roles of oxidative-antioxidative biomarkers in PH patients.

NO is synthesized in the endothelium from L-arginine by NO synthase. Asymmetric dimethylarginine (ADMA) is an endogenous NO synthase inhibitor, which has been implicated in the pathogenesis of various cardiovascular diseases [ 12- 16]. ADMA plasma levels are significantly elevated in idiopathic pulmonary arterial hypertension (IPAH), and correlated significantly with mixed-venous oxygen saturation, right atrial pressure, cardiac index, as well as survival [ 17, 18].

Whether oxidative-antioxidative biomarkers and ADMA are associated with mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance index (PVRI) remains unclear. Both oxidative-antioxidative imbalance and impaired NO signaling are involved in endothelial dysfunction and vascular remodeling. NO relaxes smooth muscle and decreases its metabolism, which will reduce the production of ROS. Thus, there may be some association between ADMA and oxidative-antioxidative biomarkers, which need to be investigated to further understand the pathogenesis and pathophysiologic processes of PH.

Therefore, we designed this case-control study to measure the oxidative-antioxidative biomarkers and ADMA level in the healthy controls, PAH patients, and CTEPH patients, with an attempt to identify the association between oxidative-antioxidative biomarkers and ADMA, simultaneously evaluate the association between these biomarkers and PH severity assessed by pulmonary hemodynamics. The level of these biomarkers was compared between PAH patients and their age- and gender-matched controls, between CTEPH patients and their age- and gender-matched controls respectively. The oxidative biomarkers we assessed included derivative of reactive oxygen molecules (d-ROMs) and malondialdehyde (MDA). Biological antioxidant potential (BAP) and superoxide dismutase (SOD) were assessed as the antioxidative biomarkers. d-ROMs and BAP, which are general evaluation of oxidative and antioxidative status respectively, have been used in the evaluation of disease severity and therapeutic effect in chronic obstructive pulmonary disease [ 19], idiopathic pulmonary fibrosis [ 20] and other diseases. ROS degrade polyunsaturated lipids, forming MDA, which is used as a biomarker to measure the level of OS in an organism [ 21, 22]. SOD out-competes damaging reactions of superoxide, protects the cell from superoxide toxicity, and is widely used in scientific research and clinical practice [ 23, 24].

Methods

Study population

Consecutive adult patients newly diagnosed with PAH or CTEPH by pulmonary angiography and right heart catheterization were enrolled. PH has been defined as an increase in mPAP ≥ 25 mmHg [ 25]. PAH is characterized by the presence of pre-capillary PH, i.e., mPAP ≥25 mmHg, pulmonary artery wedge pressure ≤15 mm Hg, and elevated pulmonary vascular resistance >3 Wood units, in the absence of other causes of pre-capillary PH. The final diagnosis of CTEPH was based on the presence of pre-capillary PH in patients with multiple chronic/organized occlusive thrombi/emboli in the elastic pulmonary arteries. Patients were excluded if they had unstable atherosclerotic vascular disease, renal dysfunction, or untreated hyperlipidemia or if they were under treatment with nitrates, NO donors, prostaglandins, endothelin receptor antagonists, sildenafil, or antioxidant therapy. The demographic and clinical information, six minute walk distance (6MWD) and WHO functional class of all the patients was recorded. mPAP and PVRI were measured by right heart catheterization.

Age- and gender-matched healthy candidates were included as the control group for PAH group and CTEPH group, respectively. Healthy controls were selected from volunteers without any abnormality in the physical examination and laboratory tests. The exclusion criteria included: 1) with a history of respiratory disease, cardiac disease, cardiovascular and cerebrovascular disease, chronic liver and kidney failure, malignancy, diabetes mellitus, and/or any additional medical disorders; 2) smoking; and 3) using antioxidant drugs.

The study protocol was approved by the Ethics Committee of Beijing Hospital (2014BJYYEC-051-01). Informed consent was obtained from each subject.

Blood samples

Once the diagnosis was established, fresh blood samples were collected before the treatment except the basic treatment began. The basic treatment included diuretics, oxygen, cardiotonics and other supportive treatment. We used the separation gel coagulation promoting vacuum tubes. Within 1 hour after sample collection, the blood sample was centrifuged by 2280 g for 5 minutes. Then the serum was stored at -80°C. All the serum samples were measured simultaneously. Before the measurement of the biomarkers, serum samples were balanced to room temperature. Thawing and refreezing were avoided.

Measurement of d-ROMs

We measured d-ROMs level using the automatic biochemical analyzer (HITACHI 7600 Series, Japan). The method is based on the principle that in Tris-HCl buffer (pH = 5), iron ions previously bonded to serum proteins can release and catalyze the conversion of serum hydroperoxides to alkoxyl and peroxyl radicals, which further react with chromogen, dimethyl para-phenylene diamine hydrochloride. Upon oxidation, its color becomes lighter, which is measured at 505 nm. Tert butyl hydroperoxide (TBHP) was used as standard substance. The results were expressed as an equivalent of mmol TBHP Equiv/L.

Measurement of BAP

BAP level was measured using the automatic biochemical analyzer (AU 5400, Olympus, Japan). The assay is based on the ability of a colored ferric thiocyanate to decrease in absorption when Fe ³⁺ ions are reduced to Fe ²⁺. The absorbance is measured photometrically at 520 nm and calculating the amount of reduced ferric ions. Vitamin C (VitC) was used as standard substance. The results were expressed as an equivalent of mmol VitC Equiv/L.

Measurement of SOD, MDA and ADMA

SOD level was measured using the automatic biochemical analyzer (AU 5400, Olympus, Japan) and a commercial kit (Fujian Luck Bioscience CO. LTD, China).

MDA and ADMA levels were measured by the method of enzyme-linked immunosorbent assay. Commercial kits (KYM, China) were used. The standard substance and serum samples were incubated with MDA/ADMA antibody. Subsequently, the peroxidase-conjugated anti-human IgG was bound to the anti-MDA/ADMA antibodies. After coloration for 15 min, the absorbance of each well was measured at 450 nm with an ultramark microplate reader (Bio-Rad, Hercules, CA). The concentration for each sample was calculated according to the standard curve, after subtraction of the blank values.

Statistical analysis

SPSS software version 17.0 (Statistical Package for the Social Sciences Inc., Chicago, IL, USA) was used to analyze all the data. Kolmogorov-Smirnov method was used to test whether the data was normal distributed. Variables were presented as mean ± standard deviation, median with quartiles, or constituent ratio as appropriate. We used t test for two independent samples or nonparametric test to compare the continuous variable and χ ² test to compare the categorical variable between groups. Pearson Correlation was used to analyze the correlation between variables. A P value < 0.05 was regarded as statistically significant.

Results

Characteristics of study population

Totally 35 patients with PH and 35 healthy controls were enrolled. Demographic data of the patients and healthy controls were presented in Table 1. Among the PH patients, 12 patients were diagnosed with PAH (7 with idiopathic PAH, 4 with connective tissue diseases associated PAH, 1 with familial PAH), and 23 were diagnosed with CTEPH. The mean age was 44.6 years in PAH group and 55.0 years in CTEPH group. In PAH group, 2 patients (16.7%) were male. In CTEPH group, 12 patients (52.2%) patients were male. Most patients in PAH and CTEPH groups were WHO functional class II-III (74.9% and 87.0%, respectively). The comorbidity, 6MWD, level of NT-proBNP and main parameters of pulmonary haemodynamics were also presented in Table 1. The median 6MWD was 253.50 m in PAH group and 275.00 m in CTEPH group, respectively.

Table 1

Characteristics of patients with PAH or CTEPH and healthy controls

Variables	PAH group (n = 12)	PAH-Control (n = 12)	Pvalue	CTEPH group (n = 23)	CTEPH-Control (n = 23)	Pvalue
Male, n (%)	2 (16.7)	2 (16.7)	1.000	12 (52.2)	11 (47.8)	0.768
Age, years	44.6 ± 13.1	44.8 ± 13.2	0.963	55.0 ± 11.6	55.7 ± 11.5	0.839
BMI, kg/m ²	25.66 ± 4.27	25.12 ± 3.73	0.894	25.75 ± 3.23	24.53 ± 3.01	0.748
Hypertension, n (%)	2 (16.7)	-	-	5 (21.7)	-	-
Diabetes Mellitus, n (%)	0 (0)	-	-	1 (4.3)	-	-
6MWD, m	253.50 (148.50, 368.25)	-	-	275.00 (150.00, 419.00)	-	-
NT-proBNP, pg/ml	1130.0 (373.9, 2312.0)	-	-	1723.0 (609.0, 3136.0)	-	-
mPAP, mmHg	50 (37, 55)	-	-	52 (49, 55)	-	-
PVRI, dyn · sec · m ² /cm ⁵	1398.0 (1149.0, 2647.5)	-	-	2231.5 (1595.75, 2611.5)	-	-
CO, L/min	3.95 ± 1.21	-	-	3.45 ± 1.19	-	-
CI, L/min/m ²	2.27 ± 0.67	-	-	1.82 ± 0.52	-	-

Data are presented as mean ± SD or median (interquartile range). PAH = pulmonary arterial hypertension; CTEPH = chronic thromboembolic pulmonary hypertension; BMI = body mass index; WHO = World Health Organization; 6MWD = 6-minute walk distance; NT-proBNP = N-terminal pro brain natriuretic peptide; mPAP = mean pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; CO = cardiac output; CI = cardiac index.

Comparison between PAH patients and PAH-controls

We compared the demographic characteristics and biomarkers level between PAH patients and PAH-controls (Table 1, Figure 1). The gender, age composition and BMI were well-matched. The mean levels of BAP and SOD were significantly lower in the PAH group compared with the control group ( P = 0.014, P < 0.001, Figure 1C and D). Patients in PAH group had significantly higher ADMA level than the control group ( P = 0.007, Figure 1E).

Comparison between CTEPH patients and CTEPH-controls

The demographic characteristics and biomarker levels were also compared between CTEPH patients and CTEPH-controls (Table 1, Figure 1). The mean level of MDA was significantly higher in CTEPH group ( P = 0.034, Figure 1B). The levels of BAP and SOD were obviously lower in the CTEPH group compared with the control group ( P = 0.015, P < 0.001, Figure 1C and D). Patients in CTEPH group had significantly higher ADMA level than the control group ( P < 0.001, Figure 1E).

Correlation analysis

We analyzed the correlation between the biomarkers (including d-ROMs, MDA, BAP, SOD and ADMA) and mPAP, PVRI, 6MWD, respectively, as well as the correlations between oxidative-antioxidative biomarkers and ADMA. The Pearson correlation coefficient and P value were listed in Tables 2, 3, 4 and 5. No significant correlation was found between oxidative-antioxidative biomarkers and ADMA (Table 2). In patients with PAH, ADMA correlated positively with mPAP (r = 0.762, P = 0.006) and PVRI (r = 0.603, P = 0.038) (Figure 2).

Table 2

The Correlation between Oxidant-antioxidant Biomarkers and ADMA

Biomarkers	PAH		CTEPH
	r	P	r	P
d-ROMs	-0.011	0.958	0.151	0.333
MDA	-0.017	0.958	0.422	0.072
BAP	-0.420	0.175	-0.333	0.164
SOD	-0.436	0.156	0.346	0.147

PAH = pulmonary arterial hypertension; CTEPH = chronic thromboembolic pulmonary hypertension; d-ROMS = derivative of reactive oxygen molecules; MDA = malondialdehyde; BAP = biological antioxidant potential; SOD = superoxide dismutase; ADMA = asymmetric dimethylarginine.

Table 3

The Correlation between the Biomarkers and mPAP

Biomarkers	PAH		CTEPH
	r	P	r	P
d-ROMs	0.174	0.610	-0.273	0.231
MDA	-0.107	0.754	0.087	0.709
BAP	-0.460	0.155	-0.132	0.569
SOD	-0.341	0.305	0.118	0.611
ADMA	0.762	0.006*	-0.097	0.700

mPAP = mean pulmonary arterial pressure; PAH = pulmonary arterial hypertension; CTEPH = chronic thromboembolic pulmonary hypertension; d-ROMS = derivative of reactive oxygen molecules; MDA = malondialdehyde; BAP = biological antioxidant potential; SOD = superoxide dismutase; ADMA = asymmetric dimethylarginine.

*The difference with control is statistically significant.

Table 4

The Correlation between the Biomarkers and PVRI

Biomarkers	PAH		CTEPH
	r	P	r	P
d-ROMs	0.352	0.353	-0.410	0.115
MDA	0.022	0.956	0.266	0.320
BAP	-0.581	0.101	-0.491	0.053
SOD	-0.654	0.056	0.043	0.875
ADMA	0.603	0.038*	-0.097	0.700

PVRI = pulmonary vascular resistance index; PAH = pulmonary arterial hypertension; CTEPH = chronic thromboembolic pulmonary hypertension; d-ROMS = derivative of reactive oxygen molecules; MDA = malondialdehyde; BAP = biological antioxidant potential; SOD = superoxide dismutase; ADMA = asymmetric dimethylarginine.

*The difference is statistically significant.

Table 5

The Correlation between the Biomarkers and 6MWD

Biomarkers	PAH		CTEPH
	r	P	r	P
d-ROMs	-0.357	0.386	-0.092	0.765
MDA	-0.071	0.867	-0.311	0.301
BAP	0.546	0.162	-0.166	0.588
SOD	0.548	0.159	0.477	0.100
ADMA	-0.454	0.259	-0.369	0.264

6MWD = 6-minute walk distance; PAH = pulmonary arterial hypertension; CTEPH = chronic thromboembolic pulmonary hypertension; d-ROMS = derivative of reactive oxygen molecules; MDA = malondialdehyde; BAP = biological antioxidant potential; SOD = superoxide dismutase; ADMA = asymmetric dimethylargininenn.

Discussion

Oxidative-antioxidative status in PH

OS, an imbalance between ROS and antioxidant molecules, has been reported to be associated with various diseases, such as diabetes [ 26] and atherosclerosis [ 27]. Hypoxia, hypoperfusion, and instability in pulmonary circulation in PH may cause OS. In animal models, OS was found to be associated with the pathogenesis and development of PH [ 10]. However, few studies have explored the application of oxidative-antioxidative biomarkers in PH patients.

BAP and d-ROMs reflect the level of total antioxidants and oxidants in the samples, respectively. Previous studies found that d-ROMs level was high in COPD patients [ 28], and was associated with the severity of IPF [ 20]. BAP level was significantly lower in patients with metabolic syndrome [ 29], and was closely associated with diabetic retinopathy and nephropathy in patients with type 2 diabetes [ 30].

The most possible reason for decreased BAP and SOD level in patients with PH is the consumption of antioxidant substances in the OS. The level of d-ROMs stayed normal in PAH and CTEPH, which was possibly in compensatory status. The finding of our study suggests that OS contributes to the pathogenesis of PAH and CTEPH. In animal models, SOD augmentation regresses experimental PAH [ 31]. The antioxidant therapy might be used as a supplement in the treatment of PH.

In a group of 347 patients who underwent echocardiographic assessment, the relationship between pulmonary artery systolic pressure (PASP) measured by echocardiography and plasma aminothiol OS markers was investigated. For each 1% increase in plasma cystine, PASP increased by 16% [ 32]. However, in our current study, we did not find correlation between oxidative-antioxidative biomarkers and mPAP or PVRI measured in right heart catheterization. One possible reason is that we used different OS biomarkers and different procedures to measure pulmonary artery pressure. Another possible reason is the limited sample size of our study. Right heart catheterization is the golden standard for PH diagnosis and mPAP is more accurate than PASP estimated in echocardiography. The relationship between OS biomarkers and pulmonary artery pressure needs to be explored in more patients who undergo right heart catheterization assessment.

Increased ADMA in PH and its significance

ADMA is a natural ubiquitous amino acid. The lungs are a major source of NO synthase and ADMA, which are in a dynamic balance and determine NO production [ 33]. ADMA has multiple functions, such as vasoconstriction, impairing endothelial-related dilatation, and increasing endothelial adhesivity [ 34]. Plasma ADMA levels are related with endothelial dysfunction. ADMA levels are elevated in many cardiovascular and metabolic diseases such as coronary artery disease [ 35] and hypertension [ 36]. In our study, ADMA level was elevated in PH, which is consistent with previous studies [ 17, 18, 37- 39]. The potential mechanism that ADMA contributes to PH has been studied recently. ADMA is metabolized by dimethyl-arginine dimethylaminohydrolase. Suppression of endothelial dimethyl-arginine dimethylaminohydrolase expression and function represents as an important underlying mechanism in hypoxia-induced PH [ 40] and IPAH [ 41]. ADMA may induce pulmonary endothelial dysfunction via changes in the expression and activity of connexin 43 [ 42].

Also in our current study, the serum ADMA level correlated positively with mPAP in PAH patients, as well as PVRI. In previous studies, plasma ADMA concentrations correlated with mixed venous saturation, right atrial pressure, and cardiac index [ 18]. These findings indicate that the down-regulation of NO/cGMP pathway plays a crucial role in PAH, and the inhibition degree of this pathway affects the disease severity. The possible explanation for this association is that the NO/cGMP pathway regulates pulmonary vascular tone, which can be reflected directly by mPAP and PVRI. The pathophysiological role of ADMA in PAH still remains to be investigated. The relationship between the ADMA and NO system is probably more complicated than currently known. Since ADMA correlates with multiple parameters of pulmonary hemodynamics, it may be useful in the evaluation of disease severity, assessment of therapeutic efficiency, and risk stratification in patients with PAH or other kinds of PH. Given the small sample size of our study, further studies are needed to explore the values of ADMA in PH.

Relationship between oxidative-antioxidative biomarkers and ADMA

Accumulating evidences have demonstrated that NO is closely associated with ROS. During chronic hypoxia, increased vascular superoxide anion production adversely impact endothelial function by impairing NO signaling [ 43]. When enough ROS are produced, they will start reacting readily with NO to form the peroxynitrite [ 44]. NO, the endothelium-derived relaxing factor, decreases smooth muscle metabolism and reduces ROS production. ADMA increases intracellular ROS generation in bovine retinal capillary endothelial cells [ 45]. In this study, we did not find association between oxidative-antioxidative biomarkers and ADMA in peripheral serum. The level of these biomarkers in peripheral circulation is a reflection of overall production and cleavage of ROS, RNS, and NO, which is more complicated and may be affected by various factors.

The pathogenesis of PH is a complex multifactorial process. OS and impaired NO/sGC/cGMP signal pathway are both involved, and their relationship is complicated. We speculate that ROS increase first, then NO decreases. The three major stimuli that drive the vascular remodeling process are inflammation, shear stress and hypoxia. All these stimuli may increase the production of ROS, which leads to low levels of tetrahydrobiopterin and L-arginine, the rate limiting co-factor and substrate for endothelial NO synthase. Then endothelial NO synthase is uncoupled, resulting in decreased NO production and increased ROS production in turn [ 9]. We think that this process happens rapidly in our body, therefore, we couldn’t detect the change of oxidative-antioxidative biomarkers before the change of NO signaling biomarkers like ADMA and vice versa.

Conclusions

In summary, the antioxidative potential decreases while serum ADMA is elevated in PAH and CTEPH patients. Increased ADMA serum levels are associated with unfavorable pulmonary hemodynamics in PAH patients. ADMA may be useful in the severity evaluation and risk stratification of PAH.

Ethics statement

The study protocol was approved by the Ethics Committee of Beijing Hospital (2014BJYYEC-051-01). Informed consent was obtained from each subject.

Funding

This work was supported by National Key Technology Research and Development Program, [Grant2011BAI11B17]; The Capital Health Research and Development Special Fund, [2011-4011-05]; National Key Technology Research and Development Program, [Grant 2012BAI05B02]; National High Technology Research and Development Program Grant 2012AA02A511].

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30(20):2493–537. CrossRefPubMed

Archer S, Rich S. Primary pulmonary hypertension: a vascular biology and translational research "Work in progress". Circulation. 2000;102(22):2781–91. CrossRefPubMed

Grobe AC, Wells SM, Benavidez E, Oishi P, Azakie A, Fineman JR, et al. Increased oxidative stress in lambs with increased pulmonary blood flow and pulmonary hypertension: role of NADPH oxidase and endothelial NO synthase. Am J Physiol Lung Cell Mol Physiol. 2006;290(6):L1069–77. CrossRefPubMed

Karuppiah K, Druhan LJ, Chen CA, Smith T, Zweier JL, Sessa WC, et al. Suppression of eNOS-derived superoxide by caveolin-1: a biopterin-dependent mechanism. Am J Physiol Lung Cell Mol Physiol. 2011;301(3):H903–11. CrossRef

Birukov KG. Cyclic stretch, reactive oxygen species, and vascular remodeling. Antioxid Redox Signaling. 2009;11(7):1651–67. CrossRef

DeMarco VG, Habibi J, Whaley-Connell AT, Schneider RI, Heller RL, Bosanquet JP, et al. Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat. Am J Physiol Lung Cell Mol Physiol. 2008;294(6):H2659–68. CrossRef

Rawat DK, Alzoubi A, Gupte R, Chettimada S, Watanabe M, Kahn AG, et al. Increased reactive oxygen species, metabolic maladaptation, and autophagy contribute to pulmonary arterial hypertension-induced ventricular hypertrophy and diastolic heart failure. Hypertension. 2014;64(6):1266–74. CrossRefPubMed

Iwata K, Ikami K, Matsuno K, Yamashita T, Shiba D, Ibi M, et al. Deficiency of NOX1/nicotinamide adenine dinucleotide phosphate, reduced form oxidase leads to pulmonary vascular remodeling. Arterioscler Thromb Vasc Biol. 2014;34(1):110–9. CrossRefPubMed

Aggarwal S, Gross CM, Sharma S, Fineman JR, Black SM. Reactive oxygen species in pulmonary vascular remodeling. Comprehensive Physiology. 2013;3(3):1011–34. PubMedPubMedCentral

10.

Villegas LR, Kluck D, Field C, Oberley-Deegan RE, Woods C, Yeager ME, et al. Superoxide dismutase mimetic, MnTE-2-PyP, attenuates chronic hypoxia-induced pulmonary hypertension, pulmonary vascular remodeling, and activation of the NALP3 inflammasome. Antioxid Redox Signaling. 2013;18(14):1753–64. CrossRef

11.

Fan YF, Zhang R, Jiang X, Wen L, Wu DC, Liu D, et al. The phosphodiesterase-5 inhibitor vardenafil reduces oxidative stress while reversing pulmonary arterial hypertension. Cardiovasc Res. 2013;99(3):395–403. CrossRefPubMed

12.

Cooke JP. ADMA: its role in vascular disease. Vascular medicine (London, England). 2005;10 Suppl 1:S11–7. CrossRef

13.

Miyazaki H, Matsuoka H, Cooke JP, Usui M, Ueda S, Okuda S, et al. Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation. 1999;99(9):1141–6. CrossRefPubMed

14.

Fujiwara N, Osanai T, Kamada T, Katoh T, Takahashi K, Okumura K. Study on the relationship between plasma nitrite and nitrate level and salt sensitivity in human hypertension : modulation of nitric oxide synthesis by salt intake. Circulation. 2000;101(8):856–61. CrossRefPubMed

15.

Stuhlinger MC, Abbasi F, Chu JW, Lamendola C, McLaughlin TL, Cooke JP, et al. Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA. 2002;287(11):1420–6. CrossRefPubMed

16.

Notsu Y, Yano S, Shibata H, Nagai A, Nabika T. Plasma arginine/ADMA ratio as a sensitive risk marker for atherosclerosis: Shimane CoHRE study. Atherosclerosis. 2015;239(1):61–6. CrossRefPubMed

17.

Kielstein JT, Bode-Boger SM, Hesse G, Martens-Lobenhoffer J, Takacs A, Fliser D, et al. Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol. 2005;25(7):1414–8. CrossRefPubMed

18.

Skoro-Sajer N, Mittermayer F, Panzenboeck A, Bonderman D, Sadushi R, Hitsch R, et al. Asymmetric dimethylarginine is increased in chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med. 2007;176(11):1154–60. CrossRefPubMed

19.

Komatsu F, Kudoh H, Kagawa Y. Evaluation of oxidative stress and effectiveness of low-dose glucocorticoid therapy on exacerbation of chronic obstructive pulmonary disease. J Gerontol A: Biol Med Sci. 2007;62(4):459–64. CrossRef

20.

Daniil ZD, Papageorgiou E, Koutsokera A, Kostikas K, Kiropoulos T, Papaioannou AI, et al. Serum levels of oxidative stress as a marker of disease severity in idiopathic pulmonary fibrosis. Pulm Pharmacol Ther. 2008;21(1):26–31. CrossRefPubMed

21.

Moore K, Roberts 2nd LJ. Measurement of lipid peroxidation. Free Radic Res. 1998;28(6):659–71. CrossRefPubMed

22.

Del Rio D, Stewart AJ, Pellegrini N. A review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress. Nutr Metab Cardiovasc Dis. 2005;15(4):316–28. CrossRefPubMed

23.

Ismail M, Hossain MF, Tanu AR, Shekhar HU. Effect of spirulina intervention on oxidative stress, antioxidant status, and lipid profile in chronic obstructive pulmonary disease patients. BioMed research international 2015. 2015;2314-6141(Electronic):486120.

24.

Margaritelis NV, Veskoukis AS, Paschalis V, Vrabas IS, Dipla K, Zafeiridis A, et al. Blood reflects tissue oxidative stress: a systematic review. Biomarkers: biochemical indicators of exposure, response, and susceptibility to chemicals. 2015;1366-5804(Electronic):1–12.

25.

Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D42–50. CrossRefPubMed

26.

Curtis JM, Grimsrud PA, Wright WS, Xu X, Foncea RE, Graham DW, et al. Downregulation of adipose glutathione S-transferase A4 leads to increased protein carbonylation, oxidative stress, and mitochondrial dysfunction. Diabetes. 2010;59(5):1132–42. CrossRefPubMedPubMedCentral

27.

Manea A, Simionescu M. Nox enzymes and oxidative stress in atherosclerosis. Front Biosci (Schol Ed). 2012;4:651–70.

28.

Markoulis N, Gourgoulianis KI, Moulas A, Gerogianni E, Molyvdas AP. Reactive oxygen metabolites as an index of chronic obstructive pulmonary disease severity. Panminerva Med. 2006;48(4):209–13. PubMed

29.

Kim JH, Baik HW, Yoon YS, Joung HJ, Park JS, Park SJ, et al. Measurement of antioxidant capacity using the biological antioxidant potential test and its role as a predictive marker of metabolic syndrome. Korean J Intern Med. 2014;29(1):31–9. CrossRefPubMedPubMedCentral

30.

Naruse R, Suetsugu M, Terasawa T, Ito K, Hara K, Takebayashi K, et al. Oxidative stress and antioxidative potency are closely associated with diabetic retinopathy and nephropathy in patients with type 2 diabetes. Saudi Med J. 2013;34(2):135–41. PubMed

31.

Archer SL, Marsboom G, Kim GH, Zhang HJ, Toth PT, Svensson EC, et al. Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation. 2010;121(24):2661–71. CrossRefPubMedPubMedCentral

32.

Ghasemzadeh N, Patel RS, Eapen DJ, Veledar E, Al Kassem H, Manocha P, et al. Oxidative stress is associated with increased pulmonary artery systolic pressure in humans. Hypertension. 2014;63(6):1270–5. CrossRefPubMedPubMedCentral

33.

Bulau P, Zakrzewicz D, Kitowska K, Leiper J, Gunther A, Grimminger F, et al. Analysis of methylarginine metabolism in the cardiovascular system identifies the lung as a major source of ADMA. Am J Physiol Lung Cell Mol Physiol. 2007;292(1):L18–24. CrossRefPubMed

34.

Vallance P, Leiper J. Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol. 2004;24(6):1023–30. CrossRefPubMed

35.

Plicner D, Mazur P, Sadowski J, Undas A. Asymmetric dimethylarginine and oxidative stress following coronary artery bypass grafting: associations with postoperative outcome. European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery. 2014;45(5):e136–41. CrossRef

36.

Fan NC, Tsai CM, Hsu CN, Huang LT, Tain YL. N-acetylcysteine prevents hypertension via regulation of the ADMA-DDAH pathway in young spontaneously hypertensive rats. BioMed research international. 2013;2013:696317. PubMedPubMedCentral

37.

Trittmann JK, Peterson E, Rogers LK, Chen B, Backes CH, Klebanoff MA, et al. Plasma asymmetric dimethylarginine levels are increased in neonates with bronchopulmonary dysplasia-associated pulmonary hypertension. J Pediatr. 2015;166(2):230–3. CrossRefPubMed

38.

Giannakoulas G, Mouratoglou SA, Gatzoulis MA, Karvounis H. Blood biomarkers and their potential role in pulmonary arterial hypertension associated with congenital heart disease. a systematic review. Int J Cardiol. 2014;174(3):618–23. CrossRefPubMed

39.

Parikh RV, Scherzer R, Nitta EM, Leone A, Hur S, Mistry V, et al. Increased levels of asymmetric dimethylarginine are associated with pulmonary arterial hypertension in HIV infection. Aids. 2014;28(4):511–9. CrossRefPubMedPubMedCentral

40.

Millatt LJ, Whitley GS, Li D, Leiper JM, Siragy HM, Carey RM, et al. Evidence for dysregulation of dimethylarginine dimethylaminohydrolase I in chronic hypoxia-induced pulmonary hypertension. Circulation. 2003;108(12):1493–8. CrossRefPubMed

41.

Pullamsetti S, Kiss L, Ghofrani HA, Voswinckel R, Haredza P, Klepetko W, et al. Increased levels and reduced catabolism of asymmetric and symmetric dimethylarginines in pulmonary hypertension. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2005;19(9):1175–7.

42.

Tsang H, Leiper J, Hou Lao K, Dowsett L, Delahaye MW, Barnes G, et al. Role of asymmetric methylarginine and connexin 43 in the regulation of pulmonary endothelial function. Pulmonary circulation. 2013;3(3):675–91. CrossRefPubMedPubMedCentral

43.

Houston M, Estevez A, Chumley P, Aslan M, Marklund S, Parks DA, et al. Binding of xanthine oxidase to vascular endothelium. Kinetic characterization and oxidative impairment of nitric oxide-dependent signaling The Journal of biological chemistry. 1999;274(8):4985–94. PubMed

44.

Kamezaki F, Tasaki H, Yamashita K, Tsutsui M, Koide S, Nakata S, et al. Gene transfer of extracellular superoxide dismutase ameliorates pulmonary hypertension in rats. Am J Respir Crit Care Med. 2008;177(2):219–26. CrossRefPubMed

45.

Chen YH, Xu X, Sheng MJ, Zheng Z, Gu Q. Effects of asymmetric dimethylarginine on bovine retinal capillary endothelial cell proliferation, reactive oxygen species production, permeability, intercellular adhesion molecule-1, and occludin expression. Mol Vis. 2011;17:332–40. PubMedPubMedCentral

Titel: Oxidative stress and nitric oxide signaling related biomarkers in patients with pulmonary hypertension: a case control study
Autoren:: Shuai Zhang
Ting Yang
Xiaomao Xu
Meng Wang
Linye Zhong
Yuanhua Yang
Zhenguo Zhai
Fei Xiao
Chen Wang
Publikationsdatum: 01.12.2015
DOI: https://doi.org/10.1186/s12890-015-0045-8
Verlag: BioMed Central
Zeitschrift: BMC Pulmonary Medicine BMC series – open, inclusive and trusted
Ausgabe 1/2015
Elektronische ISSN: 1471-2466

Neu im Fachgebiet Innere Medizin

26.02.2021 | Larynxkarzinom | Nachrichten

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Springer Medizin

Oxidative stress and nitric oxide signaling related biomarkers in patients with pulmonary hypertension: a case control study

Competing interests

Authors’ contributions

Background

Methods

Study population

Blood samples

Measurement of d-ROMs

Measurement of BAP

Measurement of SOD, MDA and ADMA

Statistical analysis

Results

Characteristics of study population

Comparison between PAH patients and PAH-controls

Comparison between CTEPH patients and CTEPH-controls

Correlation analysis

Discussion

Oxidative-antioxidative status in PH

Increased ADMA in PH and its significance

Relationship between oxidative-antioxidative biomarkers and ADMA

Conclusions

Ethics statement

Funding

Competing interests

Authors’ contributions

Neu im Fachgebiet Innere Medizin

Bei Kehlkopfkrebs nach Lungentumoren fahnden?

STEMI-Patienten: Mehrgefäßerkrankung verschlechtert Einjahresprognose nicht

Kardiovaskuläres Risiko steigt bei Frauen schon ab SBP 100 mmHg

Reizdarm – „eine absolute Unterdiagnose“

Newsletter

Springer Medizin

Competing interests

Authors’ contributions

Background

Methods

Study population

Blood samples

Measurement of d-ROMs

Measurement of BAP

Measurement of SOD, MDA and ADMA

Statistical analysis

Results

Characteristics of study population

Comparison between PAH patients and PAH-controls

Comparison between CTEPH patients and CTEPH-controls

Correlation analysis

Discussion

Oxidative-antioxidative status in PH

Increased ADMA in PH and its significance

Relationship between oxidative-antioxidative biomarkers and ADMA

Conclusions

Ethics statement

Funding

Competing interests

Authors’ contributions

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