Effect of PRDX6 gene polymorphism on susceptibility to chronic obstructive pulmonary disease in the Chinese Han population

Abstract Background To explore the relationship of peroxiredoxin6 (PRDX6) tag‐single nucleotide polymorphisms (SNPs) with susceptibility to chronic obstructive pulmonary disease (COPD) in the Chinese Han population. Methods A total of 502 patients with COPD and 481 healthy controls from nine hospitals in China were enrolled in this study. The PRDX6 tag‐SNPs were identified by linkage disequilibrium (LD) analysis in 30 healthy controls. The associations between identified tag‐SNPs and COPD risk were further evaluated. Results Four PRDX6 tag‐SNPs, including rs7314, rs34619706, rs33951697, and rs4382766, were identified in 30 healthy controls. Moreover, in the allele model, there was no statistical difference in locus in PRDX6 between patients with COPD and healthy controls (P > 0.05). However, in the recessive model, rs33951697 locus in PRDX6 gene carrier with T/T had an increased risk of COPD (odds ratio [OR] = 2.59, 95% CI = 1.06–6.33, P = 0.028). Furthermore, in the relevance analysis between genetic polymorphisms and smoking behavior and lung function indexes, we found that the number of smoked cigarettes per day and FEV1/FVC differed among different genotypes of PRDX6, rs4382766, and rs7314 (P < 0.05). Conclusion PRDX6 gene polymorphism with smoking status may contribute to the etiology of COPD in the Chinese Han population

Heterozygous Tropomodulin 3 mice have improved lung vascularization after chronic hypoxia.

The molecular mechanisms leading to high-altitude pulmonary hypertension (HAPH) remains poorly understood. We previously analyzed the whole genome sequence of Kyrgyz highland population and identified eight genomic intervals having a potential role in HAPH. Tropomodulin 3 gene (TMOD3), which encodes a protein that binds and caps the pointed ends of actin filaments and inhibits cell migration, was one of the top candidates. Here we systematically sought additional evidence to validate the functional role of TMOD3. In-silico analysis reveals that some of the SNPs in HAPH associated genomic intervals were positioned in a regulatory region that could result in alternative splicing of TMOD3. In order to functionally validate the role of TMOD3 in HAPH, we exposed Tmod3-/+ mice to 4&nbsp;weeks of constant hypoxia, i.e. 10% O2 and analyzed both functional (hemodynamic measurements) and structural (angiography) parameters related to HAPH. The hemodynamic measurements, such as right ventricular systolic pressure, a surrogate measure for pulmonary arterial systolic pressure, and right ventricular contractility (RV- ± dP/dt), increases with hypoxia did not separate between Tmod3-/+ and control mice. Remarkably, there was a significant increase in the number of lung vascular branches and total length of pulmonary vascular branches (P &lt; 0.001) in Tmod3-/+ after 4&nbsp;weeks of constant hypoxia as compared with controls. Notably, the Tmod3-/+ endothelial cells migration was also significantly higher than that from the wild-type littermates. Our results indicate that, under chronic hypoxia, lower levels of Tmod3 play an important role in the maintenance or neo-vascularization of pulmonary arteries

Hypoxia‐induced pulmonary hypertension – utilising experiments of nature

An increase in pulmonary artery pressure is a common observation in adult mammals exposed to global alveolar hypoxia. It is considered a maladaptive response that places an increased workload on the right ventricle. The mechanisms initiating and maintaining the elevated pressure are of considerable interest to understanding pulmonary vascular homeostasis. There is an expectation that identifying the key molecules in the integrated vascular response to hypoxia will inform potential drug targets. One strategy is to take advantage of experiments of nature; specifically, to understand the genetic basis for the inter-individual variation in the pulmonary vascular response to acute and chronic hypoxia. To date, detailed phenotyping of highlanders has focused on haematocrit and oxygen saturation rather that cardiovascular phenotypes. This review explores what we can learn from those studies with respect to the pulmonary circulation

Structure of a green algal photosystem I in complex with a large number of light-harvesting complex I subunits

Photosystem I (PSI) is a highly efficient natural light-energy converter, and has diverse light-harvesting antennas associated with its core in different photosynthetic organisms. In green algae, an extremely large light-harvesting complex I (LHCI) captures and transfers energy to the PSI core. Here, we report the structure of PSI-LHCI from a green alga Bryopsis corticulans at 3.49 angstrom resolution, obtained by single-particle cryo-electron microscopy, which revealed 13 core subunits including subunits characteristic of both prokaryotes and eukaryotes, and 10 light-harvesting complex a (Lhca) antennas that form a double semi-ring and an additional Lhca dimer, including a novel four-transmembrane-helix Lhca. In total, 244 chlorophylls were identified, some of which were located at key positions for the fast energy transfer. These results provide a firm structural basis for unravelling the mechanisms of light-energy harvesting, transfer and quenching in the green algal PSI-LHCI, and important clues as to how PSI-LHCI has changed during evolution

Two-stage study of lung cancer risk modification by a functional variant in the 3 '-untranslated region of SMAD5 based on the bone morphogenetic protein pathway

Increasing evidence supports a key role for the bone morphogenetic protein (BMP) signaling pathway in lung vasculogenesis and angiogenesis. Genetic variations in BMP genes have been found to be correlated with cancer risk. In particular, the mutation in the 3'-untranslated region of BMPs may significantly affect gene function, leading to cancer susceptibility. The aim of the present study was to determine whether genetic variations in the components of the BMP family are associated with lung cancer risk. A total of 314 tag single-nucleotide polymorphisms were identified in 18 genes, which are considered to either compose or regulate BMPs, and their association with lung cancer risk was evaluated in a two-stage case-control study with 4,680 cases and controls. A consistently significant association of SMAD5 rs12719482 with elevated lung cancer risk was observed in the three types of sources of populations (adjusted additive model in the combined population: Odds ratio=1.32, 95% confidence interval: 1.16-1.51). The lung cancer risk statistically significantly increased with the increasing number of variant alleles of SMAD5 rs12719482 in a dose-dependent pattern (P for trend=4.9×10-5). Consistent evidence was identified for a significant interaction between the rs12719482 and cigarette smoking, performed as either a continuous or discrete variable. These findings indicated that SMAD5 rs12719482 may be a possible candidate marker for susceptibility to lung cancer in the Chinese population.National Natural Science Foundation of China [81520108001, 81220108001, 81170052]; 973 Key Scheme of China [2015CB553406]; National Key Research and Development Project [2016YFC0903700]; Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2014); Guangdong Province Universities and Colleges Key Grant for Innovative Research [cxzd1142]; Guangzhou Municipal Research Project [201607020030]; Guangzhou Department of Education Innovative Team [13C08]; Guangzhou Department of Education Yangcheng Scholarship [12A001S]; Guangdong Natural Science Foundation [2016A030313593]; Guangzhou Municipal University Research Projects [1201430298]6 month embargo; published online: 6 November 2017This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle Cells.

Excessive pulmonary artery (PA) smooth muscle cell (PASMC) proliferation and migration are implicated in the development of pathogenic pulmonary vascular remodeling characterized by concentric arterial wall thickening and arteriole muscularization in patients with pulmonary arterial hypertension (PAH). Pulmonary artery smooth muscle cell contractile-to-proliferative phenotypical transition is a process that promotes pulmonary vascular remodeling. A rise in cytosolic Ca2+ concentration [(Ca2+) cyt ] in PASMCs is a trigger for pulmonary vasoconstriction and a stimulus for pulmonary vascular remodeling. Here, we report that the calcium homeostasis modulator (CALHM), a Ca2+ (and ATP) channel that is allosterically regulated by voltage and extracellular Ca2+, is upregulated during the PASMC contractile-to-proliferative phenotypical transition. Protein expression of CALHM1/2 in primary cultured PASMCs in media containing serum and growth factors (proliferative PASMC) was significantly greater than in freshly isolated PA (contractile PASMC) from the same rat. Upregulated CALHM1/2 in proliferative PASMCs were associated with an increased ratio of pAKT/AKT and pmTOR/mTOR and an increased expression of the cell proliferation marker PCNA, whereas serum starvation and rapamycin significantly downregulated CALHM1/2. Furthermore, CALHM1/2 were upregulated in freshly isolated PA from rats with monocrotaline (MCT)-induced PH and in primary cultured PASMC from patients with PAH in comparison to normal controls. Intraperitoneal injection of CGP 37157 (0.6 mg/kg, q8H), a non-selective blocker of CALHM channels, partially reversed established experimental PH. These data suggest that CALHM upregulation is involved in PASMC contractile-to-proliferative phenotypical transition. Ca2+ influx through upregulated CALHM1/2 may play an important role in the transition of sustained vasoconstriction to excessive vascular remodeling in PAH or precapillary PH. Calcium homeostasis modulator could potentially be a target to develop novel therapies for PAH

Hypoxia‐induced pulmonary hypertension—Utilizing experiments of nature

An increase in pulmonary artery pressure is a common observation in adult mammals exposed to global alveolar hypoxia. It is considered a maladaptive response that places an increased workload on the right ventricle. The mechanisms initiating and maintaining the elevated pressure are of considerable interest to understanding pulmonary vascular homeostasis. There is an expectation that identifying the key molecules in the integrated vascular response to hypoxia will inform potential drug targets. One strategy is to take advantage of experiments of nature; specifically, to understand the genetic basis for the inter-individual variation in the pulmonary vascular response to acute and chronic hypoxia. To date, detailed phenotyping of highlanders has focused on haematocrit and oxygen saturation rather that cardiovascular phenotypes. This review explores what we can learn from those studies with respect to the pulmonary circulation

Chronic Hypoxia Decreases Endothelial Connexin 40, Attenuates Endothelium-Dependent Hyperpolarization-Mediated Relaxation in Small Distal Pulmonary Arteries, and Leads to Pulmonary Hypertension.

Background Abnormal endothelial function in the lungs is implicated in the development of pulmonary hypertension; however, there is little information about the difference of endothelial function between small distal pulmonary artery (PA) and large proximal PA and their contribution to the development of pulmonary hypertension. Herein, we investigate endothelium-dependent relaxation in different orders of PAs and examine the molecular mechanisms by which chronic hypoxia attenuates endothelium-dependent pulmonary vasodilation, leading to pulmonary hypertension. Methods and Results Endothelium-dependent relaxation in large proximal PAs (second order) was primarily caused by releasing NO from the endothelium, whereas endothelium-dependent hyperpolarization (EDH)-mediated vasodilation was prominent in small distal PAs (fourth-fifth order). Chronic hypoxia abolished EDH-mediated relaxation in small distal PAs without affecting smooth muscle-dependent relaxation. RNA-sequencing data revealed that, among genes related to EDH, the levels of Cx37, Cx40, Cx43, and IK were altered in mouse pulmonary endothelial cells isolated from chronically hypoxic mice in comparison to mouse pulmonary endothelial cells from normoxic control mice. The protein levels were significantly lower for connexin 40 (Cx40) and higher for connexin 37 in mouse pulmonary endothelial cells from hypoxic mice than normoxic mice. Cx40 knockout mice exhibited significant attenuation of EDH-mediated relaxation and marked increase in right ventricular systolic pressure. Interestingly, chronic hypoxia led to a further increase in right ventricular systolic pressure in Cx40 knockout mice without altering EDH-mediated relaxation. Furthermore, overexpression of Cx40 significantly decreased right ventricular systolic pressure in chronically hypoxic mice. Conclusions These data suggest that chronic hypoxia-induced downregulation of endothelial Cx40 results in impaired EDH-mediated relaxation in small distal PAs and contributes to the development of pulmonary hypertension

Chronic Hypoxia Decreases Endothelial Connexin 40, Attenuates Endothelium-Dependent Hyperpolarization-Mediated Relaxation in Small Distal Pulmonary Arteries, and Leads to Pulmonary Hypertension.

Background Abnormal endothelial function in the lungs is implicated in the development of pulmonary hypertension; however, there is little information about the difference of endothelial function between small distal pulmonary artery (PA) and large proximal PA and their contribution to the development of pulmonary hypertension. Herein, we investigate endothelium-dependent relaxation in different orders of PAs and examine the molecular mechanisms by which chronic hypoxia attenuates endothelium-dependent pulmonary vasodilation, leading to pulmonary hypertension. Methods and Results Endothelium-dependent relaxation in large proximal PAs (second order) was primarily caused by releasing NO from the endothelium, whereas endothelium-dependent hyperpolarization (EDH)-mediated vasodilation was prominent in small distal PAs (fourth-fifth order). Chronic hypoxia abolished EDH-mediated relaxation in small distal PAs without affecting smooth muscle-dependent relaxation. RNA-sequencing data revealed that, among genes related to EDH, the levels of Cx37, Cx40, Cx43, and IK were altered in mouse pulmonary endothelial cells isolated from chronically hypoxic mice in comparison to mouse pulmonary endothelial cells from normoxic control mice. The protein levels were significantly lower for connexin 40 (Cx40) and higher for connexin 37 in mouse pulmonary endothelial cells from hypoxic mice than normoxic mice. Cx40 knockout mice exhibited significant attenuation of EDH-mediated relaxation and marked increase in right ventricular systolic pressure. Interestingly, chronic hypoxia led to a further increase in right ventricular systolic pressure in Cx40 knockout mice without altering EDH-mediated relaxation. Furthermore, overexpression of Cx40 significantly decreased right ventricular systolic pressure in chronically hypoxic mice. Conclusions These data suggest that chronic hypoxia-induced downregulation of endothelial Cx40 results in impaired EDH-mediated relaxation in small distal PAs and contributes to the development of pulmonary hypertension

A Functional Variant rs6435156C>T in BMPR2 is Associated With Increased Risk of Chronic Obstructive Pulmonary Disease (COPD) in Southern Chinese Population

Backgrounds: Bone morphogenetic protein receptor type 2 (BMPR2) signaling is anti-inflammatory. Decreased BMPR2 expression was seen in lung tissue from chronic obstructive pulmonary disease (COPD) patients. Methods: The selected single nucleotide polymorphisms (SNPs) in BMPR2 were genotyped with polymerase chain reaction (PCR) ligase detection reaction. The effects of SNPs on gene expression were analyzed with luciferase assays. The mRNA and protein expression levels of BMPR2 in peripheral blood mononuclear cells (PBMCs) from COPD patients were determined by quantitative PCR and western blotting, respectively. Findings: Two SNPs, rs6435156C>T and rs1048829G>T in the 3′-untranslated region (3′UTR) of BMPR2 were selected and genotyped in COPD case and healthy control subjects from southern Chinese population. Both of them were found associated with significantly increased COPD risk (adjusted odds ratio [OR] = 1.58 with 95% confidence interval [CI] = 1.14–2.15, P = 0.0056 for rs6435156C>T; adjusted OR = 1.47 and 95% CI = 1.10–1.97, P = 0.0092 for rs1048829G>T). Older age, cigarette smoking, family history of cancer and COPD were all factors that interacted with rs6435156C>T and rs1048829G>T causing increased COPD risk. Cigarette smokers with rs6435156 (CT + TT) or rs1048829 (GT + TT) were more susceptible to COPD than that with the rs6435156CC or rs1048829GG genotypes. In A549 human alveolar epithelial cells, luciferase reporter assays revealed that introduction of 3′UTR of BMPR2 plasmids carrying rs6435156T allele but not rs1048829T led to lower luciferase activity than the wild-type C or G alleles. Comparing to rs6435156CC, treatment with hsa-miR-20a mimics deceased whereas hsa-miR-20a inhibitor restored the luciferase reporter activity in cells transfected with constructs carrying rs6435156TT. BMPR2 mRNA and protein expressions were significantly lower in PBMCs from COPD smokers than that in non-smokers. COPD patients carrying rs6435156T allele had less BMPR2 expression in PBMCs. Interpretation: This study demonstrated that both rs6435156C>T and rs1048829G>T variants in BMPR2 contributed to increased susceptibility to COPD. The T variants of rs6435156 increased COPD risk likely by binding with hsa-miR-20a, thus leading to downregulated BMPR2 expression in lung epithelial and immune cells