|Year : 2019 | Volume
| Issue : 3 | Page : 349-357
Role of telomerase expression in interstitial lung diseases
Marwa M Shaban1, Radwa A Elhefny2, Sabah H Hussein2, Amul A Badr3, Zeinab A Nour3
1 Department of Chest Diseases, Cairo University, Giza, Egypt
2 Department of Chest Diseases, Fayoum University, Faiyum, Egypt
3 Department of Chemical Biochemistry and Molecular Biology, Cairo University, Giza, Egypt
|Date of Submission||01-Sep-2018|
|Date of Acceptance||19-Dec-2018|
|Date of Web Publication||26-Jul-2019|
Radwa A Elhefny
43 Gol Gamal Street, Elmohandseen, Giza 12654
Source of Support: None, Conflict of Interest: None
Background Telomeres are hexameric nucleotide sequences. The biological role of telomeres is to prevent shortening of DNA to preserve integrity of the genome. Length of telomeres is determined by age, sex, and environmental exposures. Telomeres are vulnerable to injury by oxidative stress. Telomere length is sustained by telomerase, a ribonucleoprotein telomerase reverse transcriptase (TERT). Telomerase may help cell growth and secure against cell death. ‘Telomeropathy’ is associated with genetic mutations. The most common phenotype related to telomerase mutation is pulmonary fibrosis.
Objective To investigate the associations of both TERT and telomerase RNA component C with disease progression in patients with interstitial lung diseases (ILDs), which include idiopathic pulmonary fibrosis (IPF), and to compare results between patients with ILD and control.
Patients and methods A total of 46 patients with different types of ILDs were enrolled as well as 15 healthy persons as control. Whole blood sample was obtained from both patients and healthy control for detection of expression of telomerase gene by quantitative real-time PCR.
Results There was a significant negative correlation between telomerase reverse transcriptase (h-TERT) and partial pressure of oxygen (r=−23, P=0.03). Both h-TERT and telomerase reverse transcriptaseRNA component (h-TERC) were relatively more expressed in patients with IPF with pulmonary hypertension, whereas there was a significant elevation of h-TERT relative expression in patients with IPF with honeycombing high-resolution computed tomography pattern in comparison with those with reticulonodular pattern, with median of 0.85 versus 0.29, respectively.
Conclusion Hypoxia may affect DNA damage in the telomere region. Expression of telomerase may take part in pulmonary fibrosis. Exposure to hypoxia or growth factors can stimulate the expression of telomerase on cells of vascular smooth muscle.
Keywords: interstitial lung disease, idiopathic pulmonary fibrosis, telomerase expression, telomerase, telomere gene
|How to cite this article:|
Shaban MM, Elhefny RA, Hussein SH, Badr AA, Nour ZA. Role of telomerase expression in interstitial lung diseases. Egypt J Bronchol 2019;13:349-57
| Introduction|| |
Eukaryotic chromosomes contain telomeres which have hexameric nucleotide (TTAGGG)n repeats on its distant ends . The biological role of telomeres is to prevent shortening of DNA, to provide security to the chromosomes from unsuitable fusions of DNA, and also to prevent breaks of DNA to preserve integrity and stabilization of the genome . Upon cell division, length of telomere (TL) reduces by pairs of 50–200 bases, which conjointly associates with cell aging, eventually ends in an important TL point, which promotes fusions of chromosomal and/or cell death .
TLs is determined not only by genetic but also by several other factors including sex, age, and environmental exposures . Susceptibility of telomeres to damage increases by oxidative stress because of their high content of guanine residues .
Telomerase reverse transcriptase (TERT) attaches the DNA repeats of TTAGGG to ends of telomere, thereby sustaining the TL through replication of genome. To do this function, TERT needs the template of RNA molecule telomerase RNA component C (TERC) and telomerase-associated proteins .
TERT is responsible for telomerase activity (TA), because of this fact, TA expression is hardly controlled, being greatly expressed only in tissues that regularly or continuously renew, such as in the germ cells, hematopoietic system cells, the epidermis, and tumors. In contrast to TERT, expression of TERC is broadly in all cells of any type, but cannot make TA .
Biological functions of telomerase are separate from its enzymatic activity in maintenance of telomere. Telomerase may help cell growth and preserve against cell death by using pathways not related to its telomere elongation function ,.
‘Pulmonary fibrosis’ includes a wide range of diseases of lung, including most importantly the idiopathic interstitial pneumonias (IIPs) , with idiopathic pulmonary fibrosis (IPF) being the most common and severe clinic-pathologic entity of IIPs .
Implication of the role of maintenance of TL in interstitial lung disease (ILD), especially in IIP, has been found ,.
Short telomere syndrome, or ‘telomeropathy’ is associated with genetic mutations in TERT, TERC, regulator of telomere elongation helicase 1, and poly(A)-specific ribonuclease, which can be distinguished by abnormalities of many systems including pulmonary fibrosis, bone marrow dysfunction, cirrhosis of liver, and greying at early age. Overall, pulmonary fibrosis is the most common phenotype associated with telomerase mutation . Regardless of the diagnosis, rapid disease progression and poor survival are related to this genetic mutation, which suggest that disease development, disease progression, and fibrosis propagation are related to telomere dysfunction .
TL may be partly responsible for a significant overlap between the clinical, radiographic, and histopathologic features of IPF and chronic hypersensitivity pneumonitis owing to association of short age-adjusted TL with radiographic and histopathologic ‘IPF-like features’ in the form of honeycombing, temporal heterogeneity, and fibroblastic foci .
| Aim|| |
This study tried to investigate the associations of both TERT and TERC with disease progression in patients with ILDs, including IPF, in a trial extending these considerations to human chronic fibrotic lung disease.
| Patients and methods|| |
This prospective study was conducted in chest department in collaboration with Molecular Biology and Biochemistry Department, Faculty of Medicine, Cairo and Fayoum Universities. This study included 46 patients already diagnosed with different types of ILDs (the study group) and 15 healthy control participants. All patients were subjected to full history taking including drug history, smoking and history of exposure, detailed clinical examination, arterial blood gases analysis, spirometry, high-resolution computed tomography (HRCT) of the chest to determine the pattern of lung parenchymal affection, and echocardiography to evaluate the right-side heart chamber size and to screen for associated pulmonary hypertension (PH). Moreover, serological tests were done to screen for associated autoimmune features. Whole blood sample was obtained from both patients already diagnosed to have ILD [clinical data, radiologic imaging, and pathologic findings (if lung biopsy is needed) are combined to reach the diagnosis] and healthy control participants for determination of telomerase gene expression by quantitative real-time PCR. The Human Research Ethics Committee, Faculty of Medicine, Fayoum University, has approved the study.
Detection of telomerase gene expression by quantitative real-time PCR
Extraction of total RNA
Removal of total RNA was done from whole blood using SV Total RNA Isolation System (Promega, Madison, Wisconsin, USA), according to the manufacturer’s instructions. Ultraviolet spectrophotometer was used to measure the concentrations of RNA and purity.
Synthesis of complementary DNA
SuperScript III First-Strand Synthesis System (Invitrogen, Massachusetts, USA) was used for union of the cDNA to 1 µg RNA according to the manufacturer’s protocol (#K1621; Fermentas, Waltham, Massachusetts, USA). In summary, 1 µg of total RNA was mixed with 50 µmol/l oligo (dT) 20, 50 ng/µl random primers, and 10 mmol/l dNTP mix in RNase-free water to a 10-µl total volume. This mixture is kept at 56°C for 5 min and then put on ice for 3 min. Mixing of the reverse transcriptase master was performed, which contained buffer of 2 µl of 10× RT, 4 µl of 25 mmol/l MgCl2, 2 µl of 0.1 mol/l DTT, and 1 µl of SuperScript. Addition of III RT (200 U/µl) to the mixture and placing in an incubator at 25°C for 10 min were performed followed by 50 min at 50°C.
Real-time quantitative PCR
Applied Biosystem with software version 3.1 (StepOne; USA) was used for real-time PCR amplification and analysis. The reaction contained SYBR Green Master Mix (Applied Biosystems, Foster City, CA, USA) and gene-specific primer pairs, which were primer sequences of both T and C as follow: (h-TERT) forward primer: 5′-TGACACCTCACCTCACCCAC-3′, (h-TERC) forward primer: 5′-GCCTGCCGCCTTCCACCGTTCATT-3′, and (h-TERT) reverse primer 5′-CACTGTCTTCCGCAAGTTCAC-3′, (h-TERC) reverse primer 5′-GACTCGCTCCGTTCCTCTTCCTG-3′. β-Actin sequences were as follows: forward primer: 5′-CTGTCTGGCGGCACCACCAT-3′ and reverse primer: 5′-GCAACTAAGTCATAGTCCGC-3′. They were planned with Gene Runner Software (Hasting Software Inc., Hasting, New York, USA) from RNA sequences from the bank of gene. A calculated annealing temperature of 60° was found in all primer sets. In a reaction of volume of 25 µl containing of 2X SYBR Green PCR Master Mix (Applied Biosystems), 900 nmol/l of each primer and 2 µl of cDNA; quantitative RT-PCR was used.
Conditions for amplification were as follows: 2 min at 50°, 10 min at 95° and 40 cycles of denaturation for 15 s, and annealing/extension at 60° for 10 min. Real-time assay data using the v1 · 7 sequence detection software from PE Biosystems (Foster City, California, USA) were calculated. The comparative Ct method was used to calculate the relative expression of studied gene mRNA. Normalization of all values were done to β-actin, as it was used as the housekeeping gene control and detected as fold change over background levels found in the diseased groups.
Collection, tabulation, and analyses of the statistical data were done using SPSS 22.0 for Windows (SPSS Inc., Chicago, Illinois, USA). All tests were two sided. A P value less than 0.05 was considered significant. Continuous variables were expressed as mean, SD, median and 25–75 percentile, and the categorical variables were expressed as a number (percentage). Checking for normality of continuous variables was done using Shapiro–Wilk test. Two sample t-test was used to compare between two normally distributed data, whereas Mann–Whitney test was used for two groups with nonnormally distributed data. Analysis of variance test was used to compare between more than two groups of normally distributed data, whereas Kruskall–Wallis H-test was applied to compare between more than two groups of non-normally distributed data. Categorical variables percent were compared using Pearson’s χ2-test or Fisher’s exact test when appropriate. Pearson’s correlation was calculated to assess the correlations between various study parameters, where positive sign indicates positive correlation and negative sign indicates negative correlation.
| Results|| |
This prospective study was conducted in the chest department in collaboration with Molecular Biology and Biochemistry Department, Faculty of Medicine, Cairo, and Fayoum Universities. The study included 46 patients with different types of ILDs (the study group) and 15 healthy control participants. The mean±SD age of ILD cases was 44.20±13.40 years, whereas that of control group was 44.30±12.50 years. Regarding sex distribution and smoking status, ILD cases included 11 (23.91%) males and 35 (76.09%) females, and there were five (10.87%) smokers, whereas the control group included seven (46.67%) males and eight (53.33%) females, and there were three (20%) smokers. Both cases and control were matched regarding age, sex, and smoking habits (P values of 0.98, 0.09, and 0.38, respectively).
h-TERT and h-TERC markers were relative expressed in both groups (ILD cases and healthy control participants), with mean±SD of 0.49±0.37 and 0.66±0.31, respectively, in ILD group, and 1.01±0.01 in control (P<0.001). The most important characteristics of ILD group are shown in [Table 1]. The comparison between the different histopathological subtypes of ILD is presented in [Table 2], which revealed a statistically significant difference between the different ILD histopathological subtypes regarding positivity of autoimmune profile, forced expiratory flow 25–75%, and the predominant HRCT pattern.
|Table 2 Comparison between different histopathological subtypes of interstitial lung disease study group|
Click here to view
Regarding the correlation between both markers h-TERT and h-TERC and characteristics of patients with ILD, there was a significant negative correlation between h-TERT and partial pressure of oxygen (r=−23, P=0.03), as shown in [Table 3].
|Table 3 Correlation between h-TERT and h-TERC and the characteristics of patients with interstitial lung disease|
Click here to view
Regarding effect of different characteristics of patients with IPF on h-TERT and h-TERC expression, both h-TERT and h-TERC were relative more expressed in female (n=11) than male (n=7), without significant difference, with median of 0.51 versus 0.28 and 0.74 versus 0.72, respectively ([Table 4]). Moreover, both h-TERT and h-TERC were relative more expressed in patients with IPF with history of PH (n=11) than patients without PH (n=7), without significant difference, with median of 0.51 versus 0.28 and 0.85 versus 0.72, respectively, as shown in [Table 5], whereas there was significant elevation of h-TERT relative expression in patients with IPF with honeycombing HRCT pattern (n=11) in comparison with those with reticulonodular pattern (n=7), with median of 0.85 versus 0.29, respectively (P=0.04; [Figure 1]).
|Table 4 Effect of different characteristics of patients with interstitial lung disease on h-TERT and h-TERC expression|
Click here to view
|Table 5 Effect of different characteristics of patients with idiopathic pulmonary fibrosis on h-TERT and h-TERC expressions|
Click here to view
|Figure 1 h-TERT expression in IPF patients as regarding its HRCT pattern.|
Click here to view
The best cutoff point level of h-TERT and h-TERC was 0.99; at or below the determent cutoff point of h-TERT and h-TERC, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of ILD diagnosis were 91.3, 100, 100, 79, and 93.4%, and the area under the curve was 92% for both. Regarding value of h-TERT and h-TERC in IPF diagnosis, the best cutoff point of h-TERT and h-TERC was 0.99 and 0.97, respectively; the sensitivity and specificity of h-TERT and h-TERC at this cutoff point were 94 and 100%, respectively, the area under the curve was 94% for both. At or below the determent cutoff point of h-TERT and h-TERC, the positive predictive value, negative predictive value, and accuracy of IPF diagnosis were 100, 94, and 97%, respectively.
| Discussion|| |
Over the past decades, a countless of number of human diseases including Werner syndrome, dyskeratosis congenita, Bloom syndrome, ataxia–telangiectasia, Fanconi anemia and Nijmegen breakage syndrome are showing aging of cells, which are regulated by telomerases .
Throughout the previous 5 years, the scale of diseases influenced by length disequilibrium of telomere has been greatly increased. Among these, the lung disease, IPF, is the important frequent manifestation of telomere-mediated disease .
TA is widely demonstrated in cells of cancer and unnoticed in somatic cells of adult, but it is temporarily induced in many tissues subjected to repair, injury, and fibrosis. Hypoxia, bleomycin, and silica-induced lung injury and fibrosis in rodents are marked by the promotion of telomerase in cells of epithelium and fibroblasts ,.
This study tried to investigate the associations of both TERT and TERC with disease progression in patients with ILDs, involving IPF, and tried to compare results between patients with ILD and control.
In this study, both cases and control were matched regarding age and sex, with P value of 0.98 and 0.09, respectively; therefore, there was no significant difference between them regarding age and sex.
The mean±SD age of ILD cases was 44.20±13.40 years, whereas that of control group was 44.30±12.50 years.
There was no correlation of significance between both markers h-TERT and h-TERC and the age (P=0.43 and 0.59, respectively), sex (P=0.86 and 0.76, respectively) of patients with ILD. However, the result of this study found in patients with IPF, h-TERT was relative more expressed in female (n=11) than male (n=7), without significant difference, with median of 0.51 versus 0.28.
In contrast, the study by Savale et al.  revealed that TL was shorter in control males than control females.
In general, age shortens telomeres, and their length may be affected by stressors, such as diet, physical activity, chronic inflammation, and occupational and environmental exposure and thus forming an association between TL and aging and associated diseases ,.
Different hypotheses found a relation between sex and TL. Shiel et al.  found that TL is related inversely to chronological age in humans. Gardnera et al.  found that there might be a relation between sex and TL, with females with longer telomeres than males, and that this connection might become evident with increasing age. Other hypotheses proposed that steroid of sex hormones may be a good regulator of physiology in expression of h-TERT .
Despite that oxidative stress is triggered by smoking , which may influence telomere shortening , this study found no significant correlation between h-TERT and h-TERC expression and smoking history in patients with ILD.
In contrast, previous studies by Morla et al. , Valdes et al. , and Chan et al.  revealed cigarette smoking effect on telomere shortening.
Morla et al.  found a dose–response connection between cumulative exposure to tobacco smoking in life and TL.
A study by Schulz et al.  found that the relation between TL and lung function indices in a random sample was essentially owing to smokers, which revealed that lung function mainly shows aging owing to extrinsic factors rather than intrinsic aging in the absence of substantial pollution of air.
Similarly, this study found no significant correlation between both markers h-TERT and h-TERC and extrinsic factors (as smoking and bird exposure) on pulmonary function in patients with ILD.
Moreover, the study done by Dai et al.  found that data of PFT including forced vital capacity, forced expiratory volume in 1 s, and diffusion capacity for carbon monoxide of lung revealed no differences of significance between the two groups with patients with IPF (group with TERT/TERC gene mutations and second group without TERT/TERC gene mutations).
There are two options regarding the connection between induction of hypoxia and TA. Damage of DNA in the telomere region can expand its effect by hypoxia, which would lead to expression of hypoxia-inducible factor-1-produced telomerase to save the destroyed ends of chromosome; or an antiapoptotic response may be generated by the hypoxic induction of telomerase .
Hypoxia-inducible factor-1α is the vital activating transcription factor to cause transcription of TERT, which sequentially can control the transcription of TERT and increase its expression and TA ,. Similarly our study found that there was a negative significant correlation between h-TERT and partial pressure of oxygen (r=−23, P=0.03). In contrast, other study revealed that oxidative stress may increase the shortening of telomeres of circulating leukocytes in patients with obstructive sleep apnea .
This study showed there was a significant elevation of h-TERT relative expression in patients with IPF with honeycombing HRCT pattern (n=11) in comparison with those with reticulonodular pattern (n=7), with median of 0.85 versus 0.29, respectively (P=0.04).
Similar to our study, Nozaki et al.  found that expression of telomerase may take part in pulmonary fibrosis, which revealed that the affected tissue of lung and isolated fibroblasts of lung from rats with bleomycin-induced pulmonary fibrosis is induced by TA.
In contrast Newton et al.  found that between different telomere-related genetic mutation patients, there is a poor genotype–ILD phenotype relation. The site of the lung fibrosis, the pattern of lung damage (honeycombing either microcystic vs. macrocystic), the extracellular matrix nature deposition in the lung, and the extent of re-modelling are controlled by genetic and environmental factors. For example, there is proof of fibrosis around central airway and air trapping in patients with chronic hypersensitivity pneumonitis; in these cases, more cycles of cell division and more telomere shortening of airway epithelia around the small airways of lung after inhalation of fibro-genic environmental agent exist .
This study found that both h-TERT and h-TERC were relatively more expressed in patients with IPF with history of PH (n=11) than patients without PH (n=7) without significant, with median of 0.51 versus 0.28 and 0.85 versus 0.72, respectively.
PH is a crucial complication of IPF . The principal targets that lead to growth of pulmonary vascular cells excessively, hypertrophic remodeling of the arterial wall, and PH are pulmonary artery smooth muscle cells . Expression of telomerase on vascular smooth muscle cells can be done on provocation by growth factors or subjected to hypoxia , supporting a part for telomerase in dysregulated growth of vascular cells . In contrast, a study by Mouraret et al.  found that patients with idiopathic pulmonary artery hypertension (iPAH) have excessive expression of TERT in lung and in mice with experimental PH, indicating that serotonin-transporter overexpression and not hypoxia was the essential factor responsible for telomerase expression.
This study has many limitations. First, the sample size may not have been large enough to test the associations between telomerase expression in each of the ILD subsets individually with patients characteristics and extra-pulmonary manifestations of telomere-mediated disease. Second, TL was not measured in lung tissue biopsy.
Further researches will be required to detect the possible application of predicting biomarker of gene mutations and TL for therapy and outcomes in patients with ILD, especially with IPF.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Stewart SA, Weinberg RA. Telomeres. cancer to human aging. Annu Rev Cell Dev Biol
Hewitt G, Jurk D, Marques FD, Correia Melo C, Hardy T, Gackowska A et al.
Telomeres are favoured targets of a president DNA damage in ageing and stress induced senescence. Nat Commun
Shay JW, Wright WE. Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis
Newton CA, Batra K, Torrealba J, Kozlitina J, Glazer CS, Aravena C et al.
Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive. Eur Respir J
Von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci
Armanios M, Blackburn EH. The telomere syndromes. Nat Rev Genet
Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature
Xu L, Li S, Stohr BA. The role of telomere biology in cancer. Annu Rev Pathol
Ding D, Zhou J, Wang M, Cong YS. Implications of telomere-independent activities of telomerase reverse transcriptase in human cancer. FEBS J
Du Bois RM, Kangesan I, Veeraraghavan S. Genetics of pulmonary fibrosis. Semin Respir Crit Care Med
Zoz DF, Lawson WE, Blackwell TS. Idiopathic pulmonary fibrosis: a disorder of epithelial cell dysfunction. Am J Med Sci
Snetselaar R, van Moorsel CHM, Kazemier KM, van der Vis JJ, Zanen P, van Oosterhout MFM, Grutters JC. Telomere length in interstitial lung diseases. Chest
Waisberg DR, Parra ER, Barbas-Filho JV, Fernezlian S, Capelozzi VL. Increased fibroblast telomerase expression precedes myofibroblast alpha-smooth muscle actin expression in idiopathic pulmonary fibrosis. Clinics (Sao Paulo)
Armanios M. Telomerase and idiopathic pulmonary fibrosis. Mutat Res
Ley B, Newton CA, Arnould I, Elicker BM, Henry TS, Vittinghoff E et al.
The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study. Lancet Respir Med
Kong CM, Lee XW, Wang X. Telomere shortening in human diseases. FEBS J
Nozaki Y, Liu T, Hatano K, Gharaee-Kermani M, Phan SH. Induction of telomerase activity in fibroblasts from bleomycin-injured lungs. Am J Respir Cell Mol Biol
Kim JK, Lim Y, Kim KA, Seo MS, Kim JD, Lee KH, Park CY. Activation of telomerase by silica in rat lung. Toxicol Lett
Savale L, Chaouat A, Bastuji-Garin S, Marcos E, Boyer L, Maitre B et al.
Shortened telomeres in circulating leukocytes of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med
Shoeb M, Kodali VK, Farris BY, Bishop LM, Meighan TG, Salmen R et al.
Oxidative stress,DNA methylation, and telomere length changes in peripheral blood mononuclear cells after pulmonary exposure to metal-rich welding nanoparticles
Rizvi S, Raza ST, Mahdi F. Telomere length variations in aging and age-related diseases. Curr Aging Sci
Shiels PG, McGlynn LM, MacIntyre A, Johnson PCD, Batty GD, Burns H et al.
Accelerated telomere attrition is associated with relative household income, diet and inflammation in the pSoBid cohort. PLoS One
Gardner M, Bann D, Wiley L, Cooper R, Hardy R, Nitsch D et al.
Gender and telomere length: systematic review and meta-analysis. Exp Gerontol
Misiti S, Nanni S, Fontemaggi G, Cong YS, Wen J, Hirte HW et al.
Induction of hTERT expression and telomerase activity by estrogens in human ovary epithelium cells. Mol Cell Biol
Van der Vaart H, Postma DS, Timens W, ten Hacken NH. Acute effects of cigarette smoke on inflammation and oxidative stress: a review
Morla M, Buequets X, Pons J, Sauleda J, MacNee W, Agusti AG. Telomere shortening in smokers with and without COPD. Eur Respir J
Valdes AM, Andrew T, Gardner JP, Kimura M, Oelsner E, Cherkas LF et al.
Obesity, cigarette smoking, and telomere length in women. Lancet
Chan SW, Blackburn EH. New ways not to make ends meet: telomerase, DNA damage proteins and heterochromatin
Schulz H, Albrecht E, Behr J, Huber RM, Nowak D, Klopp N et al.
Are spirometric lung function indices associated with telomere length of circulating leukocytes? Pneumologie
Dai J, Cai H, Zhugang Y, Wu Y, Min H, Li J et al.
Telomerase gene mutations and telomere length shortening in patients with idiopathic pulmonary fibrosis in a Chinese population. Respirology
Fragkiadaki P, Tsoukalas D, Fragkiadoulaki I, Psycharakis C, Nikitovic D, Spandidos DA, Tsatsakis AM. Telomerase activity in pregnancy complications (Review). Mol Med Rep
Coussens M, Davy P, Brown L, Foster C, Andrews WH, Nagata M, Allsopp R. RNAi screen for telomerase reverse transcriptase transcriptional regulators identifies HIF1 alpha as critical for telomerase function in murine embryonic stem cells. Proc Natl Acad Sci USA
Yang K, Zheng D, Deng X, Bai L, Xu Y, Cong YS. Lysophosphatidic acid activates telomerase in ovarian cancer cells through hypoxia-inducible factor-1 alpha and the PI3K pathway. J Cell Biochem
Kim KS, Kwak JW, Lim SJ, Park YK, Yang HS, Kim HJ. Oxidative stress-induced telomere length shortening of circulating leukocyte in patients with obstructive sleep apnea. Aging Dis
Sadek SH, Kasem SM. Factors predicting pulmonary hypertension in idiopathic pulmonary fibrosis patients. Egypt J Bronchol
Morrell NW, Adnot S, Archer SL, Dupuis J, Jones PL, MacLean MR et al.
Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol
Minamino T, Kourembanas S. Mechanisms of telomerase induction duringvascular smooth muscle cell proliferation. Circ Res
Marsboom G, Archer SL. Pathways of proliferation: new targets to inhibit the growth of vascular smooth muscle cells. Circ Res
Mouraret N, Houssaïni A, Abid S, Quarck R, Marcos E, Parpaleix A et al.
Role for telomerase in pulmonary hypertension. Circulation
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]