|Year : 2016 | Volume
| Issue : 2 | Page : 14-20
Galectin-3: A potential biomarker in pulmonary arterial hypertension
Jie Song1, Xiaohui Li2, Bin Liu1, Tangzhiming Li1, Zaixin Yu1
1 Department of Cardiology, Xiangya Hospital, Central South University, Changsha, China
2 Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China
|Date of Web Publication||26-Dec-2018|
Prof. Zaixin Yu
Department of Cardiology, Xiangya Hospital, Central South University, 87 Xiangya Road, 410008 Changsha
Source of Support: None, Conflict of Interest: None
Objectives: Pulmonary arterial hypertension (PAH) is a syndrome resulting from a restricted flow through the pulmonary arterial circulation, giving rise to increased pulmonary vascular resistance (PVR) and ultimately right heart failure. Previous reports have suggested that Galectin-3 (Gal-3) induced endothelial cell morphogenesis and regulated myofibroblast activation. The aim of this study was to determine the diagnostic utility of circulating Gal-3 as a potential biomarker of disease severity in PAH. Methods: Gal-3 was measured in plasma from 31 patients with PAH, diagnosed from the right heart catheterization as well as 18 healthy controls by ELISA. Chronic hypoxia-induced pulmonary hypertension models were established in Sprague-Dawley rats. Lung tissues were collected for histological analysis including Gal-3 lung qualitative localization by immunohistochemistry. Total mRNA was extracted from pulmonary arteries in rats and quantitative polymerase chain reaction was performed with total cellular mRNA to measure Gal-3 expression. Results: Plasma level of Gal-3 was significantly decreased in PAH patients compared with healthy controls (P < 0.001). Within the subgroups, only by idiopathic PAH (IPAH) patients expressed the lower level of Gal-3 (n = 16, P < 0.001). Gal-3 levels were inversely correlated with mean pulmonary arterial pressure (mPAP) (r = − 0.570, P = 0.021) and PVR (r = − 0.550, P = 0.027), and correlated with cardiac output (r = 0.530, P = 0.035) in IPAH patients. A Gal-3 cutoff value <1.765 ng/ml yielded 93% sensitivity and 88% specificity for IPAH patients. Immunohistochemistry identified Gal-3 distribution throughout the adventitia of the pulmonary arterioles. The expression of Gal-3 mRNA was significantly downregulated in the pulmonary arteries from lung tissue samples in pulmonary hypertension rats. Conclusions: Gal-3 might be involved in the pathogenesis of PAH and plasma Gal-3 could serve as a promising new biomarker of diagnosis and disease severity in IPAH.
Keywords: Galectin-3, pulmonary hypertension, pulmonary vascular remodeling
|How to cite this article:|
Song J, Li X, Liu B, Li T, Yu Z. Galectin-3: A potential biomarker in pulmonary arterial hypertension. Cardiol Plus 2016;1:14-20
| Introduction|| |
Pulmonary arterial hypertension (PAH) is a life-threatening disorder characterized by a persistent increase in pulmonary artery resistance due to progressing small pulmonary artery lesions and results in deteriorating heart and lung function., Pathological characteristics of PAH such as endothelial dysfunction, fibrotic and smooth muscle cell activation, pulmonary vascular remodeling, and thrombosis lead to increased pulmonary arterial pressure and right heart overload. Hemodynamic parameters measured by the right heart catheterization have been identified and correlated to PAH prognosis and disease severity. However, a major limitation of this technique is that the parameters are obtained using an invasive approach.
Galectin-3 (Gal-3) belongs to a family of proteins that share a binding affinity for β-galactoside carbohydrates. It can be expressed and secreted by macrophages, endothelial cells, and fibroblasts and has been identified in a variety of internal cell compartments, on the membrane surface, and in the extracellular matrix and serum. Gal-3 plays important regulatory roles in cellular processes such as adhesion, proliferation, apoptosis, and signaling reactions. These functions are linked to the ability of Gal-3 to interact with a variety of ligands in the extracellular matrix. A previous study demonstrated that Gal-3 modulates basic fibroblast growth factor and vascular endothelial growth factor (VEGF)-mediated αvβ3 integrin signaling. Wesley et al. have shown that Gal-3 can mediate angiogenesis and migration of BV2 microglia through an integrin-linked kinase signaling pathway and other studies have suggested that Gal-3 may represent an important mediator for the development of organ fibrosis, such as cardiac and idiopathic pulmonary fibrosis.In vitro, Gal-3 is an important regulator in the pathogenesis of lung fibrosis by a SMAD-independent pathway through activation of transforming growth factor-beta (TGF-β) induced β-catenin. In mouse models, it has been suggested that Gal-3 may play a critical role in aldosterone-induced vascular inflammation as well as vascular remodeling. Moreover, Taniguchi et al. showed low serum Gal-3 levels in systemic sclerosis patients and relatively higher levels in patients with elevated right ventricular systolic pressure (RVSP) when compared with those without this symptom.
Currently, few studies focus on the role of Gal-3 in the physiological and pathological processes of PAH as well as its potential involvement in the pathophysiological mechanisms in the development and progression of PAH. Therefore, our hypothesis was that Gal-3 may be a new important factor in PAH. The aim of this study was to investigate the plasma levels of Gal-3 as a possible biomarker in a cohort of PAH patients and the expression of Gal-3 in hypoxia-induced PAH rat models and to determine whether plasma levels of Gal-3 correlated with disease severity in patients with PAH.
| Methods|| |
Participants and clinical assessment
Patients were enrolled from April 2012 to October 2013 in Xiangya hospital (Xiangya hospital, Hunan, China). In all patients, PAH was diagnosed based on a standard guideline,, excluded from other forms of pulmonary hypertension and confirmed by right heart catheterization. Clinical assessment of patients included medical history collection, physical examination, blood tests, chest X-ray, 12-lead electrocardiogram, echocardiography, and/or pulmonary angiography if necessary. All catheter measures were done for diagnostic reasons unrelated to this study. Hemodynamic parameters measured by right heart catheterization included mPAP, pulmonary capillary wedge pressure, mean right atrial pressure, pulmonary vascular resistance (PVR), and cardiac output (CO). The World Health Organization Functional Class (WHO FC), 6-min walking distance, Borg score, and other laboratory data were also measured. The health blood donors were recruited at the health center in Xiangya Hospital matched the sex and age of the PAH patients. The study was approved by a local ethical committee and all participants gave written informed consent.
Blood sampling and laboratory analyses
Venous blood was collected and immediately placed at −4°C at the time of right heart catheterization before the introduction of any PAH-targeted therapy. Plasma samples were prepared within 4 h using centrifugation (20 min at 3000 g) and stored at −80°C until use.
Qualification of circulating galectin-3
Plasma Gal-3 was evaluated in all PAH patients. Quantitative detection of Gal-3 was determined using a highly sensitive and specific enzyme-linked immunosorbent assay kits (Bender MedSystems, Austria) and was performed according to the manufacturer's instruction. Plasma Gal-3 was detected in healthy controls by the same assays. All assays were measured in duplicate and were performed by investigators blinded to the patients' characteristics.
Rat models and hemodynamic evaluation
Age- and weight-matched male Sprague-Dawley rats were randomized to the normoxia (n = 10) and hypoxia (n = 10) groups. All experimental procedures were approved by the Local Animal Care Committee of the Central South University. The hypoxia group was kept in a normobaric hypoxic chamber (FiO210% O2) for 21 days. Animals were euthanized immediately after hemodynamic assessment. The hearts and lungs were flushed with normal saline and removed for further analyses. Half of the lungs were fixed in situ in the distended state by infusion of 4% paraformaldehyde solution into the pulmonary artery for 24 h and then were placed in 0.2% sodium azide solution before being embedded in paraffin. Pulmonary arteries were dissected and kept in Trizol for further RNA analysis.
After 21 days, rats were anesthetized with intramuscular pentobarbital sodium (60 mg/kg). Catheters were placed into the right jugular vein, right ventricle, and pulmonary artery. The RVSP and mPAP were measured with pressure transducers. In addition, the body weight of rats was recorded, and the heart was removed and the right ventricular free wall was dissected from the left ventricle plus septum (LV + S) and weighted separately. The assessment of the right ventricular hypertrophy (RVH) degree was determined from the ratio RV/(LV + S).
Polymerase chain reaction in pulmonary artery issue
Total RNA of rat pulmonary artery tissue was extracted from Trizol reagent. Gal-3 expression levels were analyzed in main pulmonary artery tissue from hypoxia rats and normoxia control groups. Reverse transcription was performed with the PrimeScript RT kit (TaKaRa, Japan). Synthesized complementary DNA was amplified by quantitative real-time polymerase chain reaction (qPCR) using an ABI 7300 Real-Time PCR System (ABI Applied Biosystems, Foster City, USA) with SYBR Premix Ex Taq™ II Real-time PCR kit (TaKaRa, Japan) and commercially available primers. Measurements were replicated three times. Data were evaluated by calculating relative expression levels using theΔΔ CT-method. The ratio of a specific gene to β-actin was calculated in each sample.
Lung tissues were dehydrated and embedded in paraffin and sliced into 5 μm thick sections. Sections were stained with hematoxylin and eosin and Masson as per manufacturer's instruction. Gal-3 and Tenascin-C immunohistochemistry were also performed on normoxic and hypoxic sections from rats using the following primary antibodies: mouse monoclonal anti-rat Gal-3 antibody (Abcam Inc., UK) and goat anti-rat Tenascin-C antibody (Santa Cruz Biotechnology, USA).
Data analysis and statistics
Data are presented as absolute numbers and percentages and means with standard deviations. One-way analysis of variance followed by the least significant difference test was used for parametric comparisons between groups (n > 2). A two-tailed Student's t-test was performed to evaluate difference between two groups. The relationship between the Gal-3 and hemodynamic parameters was investigated using a Pearson's product-moment or Spearman's rank correlation. A receiver operating characteristic (ROC) curve was constructed to determine optimal threshold value for plasma Gal-3. Areas under ROC curves (AUCROC) and 95% confidence intervals were calculated to assess the effectiveness of Gal-3 as marker. All tests were two sided and P = 0.05 was considered statistically significant. Data analysis was performed using SPSS 17.0 (SPSS Inc., Chicago, IL, USA) and figures were prepared using the GraphPad Prism (GraphPad Prism Software Inc., San Diego, CA, USA).
| Results|| |
In total, 31 PAH patients and 18 healthy controls were enrolled in the study. Of the cohort of patients group, 16 had idiopathic PAH (IPAH), 10 had connective tissue diseases associated PAH (CTD-PAH), and 5 suffered from congenital heart diseases associated PAH (CHD-PAH). The patients group consisted of 6 men and 25 women with an average age of 34.33 ± 11.80 years. Controls were not different with respect to age, gender, and body mass index. Demographic, hemodynamic, clinical, and biochemical characteristics of patients and controls are summarized in [Table 1].
|Table 1: Clinical characteristics of patients with pulmonary arterial hypertension and healthy controls|
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Plasma levels of galectin-3 in pulmonary arterial hypertension
The mean level of Gal-3 was apparently lower in patients with PAH compared with healthy controls (2.53 ± 2.42 vs. 4.86 ± 0.94 ng/mL; P < 0.001). Moreover, the IPAH subgroup showed a much lower concentration of Gal-3 compared with healthy controls (0.95 ± 0.58 vs. 4.86 ± 0.94 ng/mL; P < 0.001). However, no differences were detected between CTD-PAH group and healthy controls (4.14 ± 2.78 vs. 4.86 ± 0.94 ng/mL; P = 0.623), neither in CHD-PAH patients 4.36 ± 2.16 vs. 4.86 ± 0.94 ng/mL; P = 0.889) [Figure 1].
|Figure 1: Plasma galectin-3 levels in patients with pulmonary arterial hypertension and healthy controls. HC: healthy controls; PAH: pulmonary arterial hypertension; IPAH: idiopathic pulmonary arterial hypertension; CTD-PAH: connective tissue diseases associated PAH; CHD-PAH: congenital heart diseases associated PAH. ***P < 0.001 versus control|
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Galectin-3 correlates with disease severity
Next, we investigated the relation of circulating Gal-3 and disease severity. There is a tendency that the level of Gal-3 decreases with the mPAP value, but the correlation analyses showed no statistically significance between Gal-3 and PAP (r = − 0.190, P = 0.324) or PVR (r = − 0.257, P = 0.178). However, in the IPAH subgroup, plasma Gal-3 was illustrated by a close negative correlation with mPAP (r = − 0.570, P = 0.021), PVR (r = − 0.550, P = 0.027), and positive correlation to CO (r = 0.530, P = 0.035) [Figure 2]. However, there was no significant correlation between Gal-3 concentrations and C-reactive protein. Similarly, no significant correlations were found between Gal-3 and 6MWD, WHO FC, Borg score, and disease duration [Table 2].
|Figure 2: Plasma galectin-3 correlates with disease severity in idiopathic pulmonary arterial hypertension. Scatter plots showing the relation of galectin-3 to mean pulmonary artery pressure, pulmonary vascular resistance, mean right atrium pressure, and cardiac output. *P < 0.05 versus control|
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|Table 2: Correlations between galectin-3 and clinical parameters in idiopathic pulmonary arterial hypertension patients|
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Plasma galectin-3 as a screening biomarker for IPAH
Mean plasma Gal-3 concentrations in the IPAH and healthy controls were 0.95 ± 0.58 ng/mL and 4.86 ± 0.94 ng/mL, respectively. The AUCROC was 0.96 (P < 0.001). Using a threshold of 1.77 ng/mL, Gal-3 maximized true-positive and false-negative results (sensitivity 93.8% and specificity 88.0%) [Figure 3].
|Figure 3: Receiver operating characteristics curves for galectin-3 in idiopathic pulmonary arterial hypertension. The area under the receiver operating characteristic curve was 0.96 (P < 0.001). The threshold concentration of 1.77 ng/mL. Galectin-3 that maximized true-positive and false-negative results (sensitivity 93.8% and specificity 88.0%)|
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Development of pulmonary hypertension with hypoxia
Hemodynamic studies in rats exposed to chronic hypoxia over 21 days demonstrated a difference in the elevation of pulmonary arterial pressure. Compared with normoxia rats group, hypoxic exposure led to an increase of mean RVSP, mPAP, and RVH [Figure 4]. Hematoxylin and eosin staining showed extensive morphological alterations of the small pulmonary arteries of rats exposed to hypoxia and included medial and intimal thickening and concentric lesions [Figure 5]. In addition, more extensive fibrosis lesions were observed in hypoxic group compared to the normoxic group determined by Masson staining [Figure 5].
|Figure 4: Hemodynamic analysis between the normoxia and hypoxia rat group. RVSP: right ventricular systolic pressure; mPAP: mean pulmonary arterial pressure; RV: right ventricular free wall; BW: body weight; LV + S: left ventricle plus septum. ***P < 0.001 versus control|
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|Figure 5: The H and D staining and Masson staining in lung tissue sections between the normoxia and hypoxia rat group. Magnification, ×200; scale bars, 100 μm|
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The downregulated expression of galectin-3 in pulmonary arteries of hypoxia-induced pulmonary arterial hypertension rats
Hypoxia-induced PAH rat models were successfully established. To clarify the cellular origin of decreased circulating Gal-3, we identified the protein expression of Gal-3 in the lung tissue from hypoxia-induced PAH rats. As a result, the localizations of Gal-3 and Tenascin-C were both mainly distributed throughout the adventitia of the pulmonary arterioles. Compared with normoxic rats, Gal-3 protein expression was downregulated in small pulmonary arteries in the hypoxia group [Figure 6]. Consistently, mRNA value was significantly decreased in pulmonary arteries in hypoxia rats compared with normoxic rats (n = 5, P < 0.01). However, Tenascin-C expression of PAH group was upregulated in pulmonary arteries and extracellular matrix with the increased mRNA level compared with the normoxia group (n = 5, P < 0.01) [Figure 6].
|Figure 6: Galectin-3 and Tenascin-C protein expression changed in rat lung after exposure to chronic hypoxia. (a-c) qualitative analysis and localization of galectin-3 expression in lung vessels sections; (d-f) qualitative analysis and localization of Tenascin-C expression in lung vessels sections; (c and f) data of mRNA expression were evaluated by calculating relative expression levels using the ΔΔCT-method in pulmonary arteries in the normoxia group and hypoxia-induced pulmonary arterial hypertension group. **P < 0.01 versus control. Magnification, ×200; scale bars, 100 μm|
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| Discussion|| |
This is the first comprehensive study on circulating Gal-3 in PAH in China. Compared with healthy control patients, PAH patients had reduced levels of Gal-3. Importantly, Gal-3 correlated with disease severity. Downregulated mRNA and protein expression were exclusive features in the PAH rat model. These findings implicate Gal-3 in the pathogenesis of PAH and questions if the plasma level of Gal-3 may be a useful biomarker for PAH.
Previous studies have reported elevated levels of Gal-3 in cardiac fibrosis, kidney fibrosis, hepatic fibrosis, and other fibrosis disease; however, we observed decreased plasma Gal-3 levels in PAH patients. Other studies have demonstrated that Gal-3 may be a mediator for the development of fibrosis and play a role in inflammation. However, decreased serum Gal-3 levels have also been reported in asthma and systemic sclerosis.
Gal-3 fulfills several prerequisites of a useful biomarker since hemodynamics, and especially PVR, are the main characteristics of PAH and reflect the severity of disease development. A tight correlation between Gal-3 and established hemodynamic parameters is extremely valuable in the evaluation of PAH disease severity.
Recent studies focus on the role of Gal-3 in the development of fibrosis, cell inhesion, and angiogenesis. As the major Gal-3-binding protein, integrin αvβ3 also binds to the VEGF receptor 2. This interaction may explain why VEGF-stimulated angiogenesis is reduced in Gal-3 knockout cells. However, the VEGF-related angiogenesis process is paradoxical; although VEGF and VEGF receptor 2 are robustly expressed in the complex vascular lesions in the lungs from patients with PAH, treatment of rodents with an anti-angiogenic VEGF receptor blocker caused angio-obliterative PAH. It is difficult to clarify the positive or negative effects of Gal-3 in the function of VEGF-regulated angiogenesis, and there is a need for further analysis of Gal-3 in the angiogenesis of PAH to identify its role.
Immunohistochemistry demonstrated that Gal-3 was expressed mainly in the adventitia and the peripheral environment between cells. It is well known that in the extracellular matrix, Gal-3 plays an important role in the cell adhesion, proliferation, and angiogenesis. In a mouse model of TGF-β-induced pulmonary fibrosis, degree of fibrosis was clearly reduced in the Gal-3 knock-out model, which showed that Gal-3 mediated the TGF-β/β-catenin pathway leading to fibrosis. In this study, we observed reduced Gal-3 expression; however, expression of Tenascin-C, another extracellular matrix protein, was increased. It may be possible that more Gal-3 proteins are bound to ligands resulting in lower amounts of the unconjugated form. Another possible explanation for the decreased level of Gal-3 may due to its binding stability. It is thought that Gal-3 can destabilize the integrin, an important cell adhesion protein in the extracellular matrix, or cause internalization or clustering, as opposed to directly regulating its expression., It is already showed that Gal-3 knock-out RL95-2 cells could lead to decreased proliferation by significantly increasing integrinβ3 expression, but these mechanisms in the pulmonary artery require further exploration in the future studies.
An important limitation of the present study is the small sample size of the cohort. Since PAH is a rare disease, a limited collection of patients may cause the absence of robust statistical evidence. In addition, the samples we could collect were limited to the blood and analyzing lung tissue from patients for the expression of Gal-3 would be more relevant. It is difficult to acquire prognosis materials from patients due to the short time of observation to make the survival analysis. Future studies should include more patients and focus on the combination of multiple markers to accurately reflect the severity of disease and prognosis.
| Conclusion|| |
The plasma Gal-3 levels are reduced in PAH, especially in IPAH. Lower circulating Gal-3 concentrations are associated with compromised hemodynamic characteristics in IPAH. Animal data suggest that Gal-3 may be involved in the pathophysical mechanisms of pulmonary hypertension. Therefore, it could be suggested that Gal-3 may be a potent new biomarker in IPAH.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]