scholarly journals A Wrinkle in Time: Circadian biology in pulmonary vascular health and disease

2021 ◽  
Author(s):  
Andrew J Bryant ◽  
Elnaz Ebrahimi ◽  
Amy Nguyen ◽  
Christopher A Wolff ◽  
Michelle L Gumz ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Large Degree ◽  
Systemic Hypertension ◽  
Pulmonary Vascular Disease ◽  
Valuable Insight ◽  
Four Dimensions ◽  
The Core ◽  
Specific Effects ◽  
Circadian Biology

An often over looked element of pulmonary vascular disease is time. Cellular responses to time, which are regulated directly by the core circadian clock, have only recently been elucidated. Despite an extensive collection of data regarding the role of rhythmic contribution to disease pathogenesis (such as systemic hypertension, coronary artery and renal disease), the roles of key circadian transcription factors in pulmonary hypertension remain under-studied. This is despite a large degree of overlap in the pulmonary hypertension and circadian rhythm fields, including not only shared signaling pathways, but also cell-specific effects of the core clock that are known to result in both protective and adverse lung vessel changes. Therefore, the goal of this review is to summarize the current dialogue regarding common pathways in circadian biology, with a specific emphasis on its implications in the progression of pulmonary hypertension. In this work, we emphasize specific proteins involved in the regulation of the core molecular clock while noting the circadian cell-specific changes relevant to vascular remodeling. Finally, we apply this knowledge to the optimization of medical therapy, with a focus on sleep hygiene and the role of chronopharmacology in patients with this disease. In dissecting the unique relationship between time and cellular biology, we aim to provide valuable insight into the practical implications of considering time as a therapeutic variable. Armed with this information, physicians will be positioned to more efficiently utilize the full four dimensions of patient care, resulting in improved morbidity and mortality of pulmonary hypertension patients.

Role of Early Pulmonary Hypertension as a Risk Factor for Late Pulmonary Hypertension in Extremely Preterm Infants

2017 ◽  
Vol 35 (02) ◽  
pp. 120-126 ◽  
Author(s):  
Dinushan Kaluarachchi ◽  
Kaitlin Woo ◽  
Tarah Colaizy
Keyword(s):  
Pulmonary Hypertension ◽  
Risk Factor ◽  
Preterm Infants ◽  
Clinical Suspicion ◽  
Pulmonary Vascular Disease ◽  
University Of Iowa ◽  
Extremely Preterm ◽  
Extremely Preterm Infants ◽  
The University

Objective The evidence on the role of early pulmonary vascular disease (PVD) in the development of late pulmonary hypertension (PH) in the extremely preterm infants is limited. Objectives were to determine the incidence of early and late PH in extreme preterm infants and to evaluate the role of early PH as a risk factor for development of clinically detected late PH. Methods It was a retrospective analysis of early echocardiograms (day of life 5–14) in preterm infants, 22 to 27 weeks' gestation, admitted to the University of Iowa NICU between July 01, 2012 to June 30, 2015. Late echocardiograms performed for clinical suspicion of PH were also analyzed. Results A total of 154 infants were included in the study. Early PH was diagnosed in 31 (20%) infants. Twenty-four (16%) infants were evaluated for clinically suspected PH. Eight (5%) infants were diagnosed with late PH. Infants with early PH had echocardiograms performed earlier than infants without the evidence of early PH. Early PH was not associated with the development of late PH (p = 0.99). Conclusion Early PH is common among extremely preterm infants (20%). Five percent of infants had clinically detected late PH. Infants with early PH had echocardiograms performed earlier than infants without the evidence of early PH. Early PH was not associated with the development of clinically detected late PH.

scholarly journals The role of RNA m6A methylation in the regulation of postnatal hypoxia-induced pulmonary hypertension

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shanshan Xu ◽  
Xuefeng Xu ◽  
Ziming Zhang ◽  
Lingling Yan ◽  
Liyan Zhang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Lung Development ◽  
Weight Ratio ◽  
Pulmonary Vasculature ◽  
Pulmonary Vascular Disease ◽  
Postnatal Exposure ◽  
Sprague Dawley ◽  
Adult Rats ◽  
The Impact

Abstract Background Pulmonary hypertension (PH) is a complex pulmonary vascular disease characterized by an imbalance in vasoconstrictor/vasodilator signaling within the pulmonary vasculature. Recent evidence suggests that exposure to hypoxia early in life can cause alterations in the pulmonary vasculature and lead to the development of PH. However, the long-term impact of postnatal hypoxia on lung development and pulmonary function remains unknown. N6-methyladenosine (m6A) regulates gene expression and governs many important biological processes. However, the function of m6A in the development of PH remains poorly characterized. Thus, the purpose of this investigation was to test the two-fold hypothesis that (1) postnatal exposure to hypoxia would alter lung development leading to PH in adult rats, and (2) m6A modification would change in rats exposed to hypoxia, suggesting it plays a role in the development of PH. Methods Twenty-four male Sprague–Dawley rats were exposed to a hypoxic environment (FiO2: 12%) within 24 h after birth for 2 weeks. PH was defined as an increased right ventricular pressure (RVP) and pathologic changes of pulmonary vasculature measured by α-SMA immunohistochemical staining. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) was performed to analyze m6A modification changes in lung tissue in 2- and 9-week-old rats that were exposed to postnatal hypoxia. Results Mean pulmonary arterial pressure, lung/body weight ratio, and the Fulton index was significantly greater in rats exposed to hypoxia when compared to control and the difference persisted into adulthood. m6A methyltransferase and demethylase proteins were significantly downregulated in postnatal hypoxia-induced PH. Distinct m6A modification peak-related genes differed between the two groups, and these genes were associated with lung development. Conclusions Our results indicate postnatal hypoxia can cause PH, which can persist into adulthood. The development and persistence of PH may be because of the continuous low expression of methyltransferase like 3 affecting the m6A level of PH-related genes. Our findings provide new insights into the impact of postnatal hypoxia and the role of m6A in the development of pulmonary vascular pathophysiology.

scholarly journals Divergent changes of p53 in pulmonary arterial endothelial and smooth muscle cells involved in the development of pulmonary hypertension

2019 ◽  
Vol 316 (1) ◽  
pp. L216-L228 ◽  
Author(s):  
Ziyi Wang ◽  
Kai Yang ◽  
Qiuyu Zheng ◽  
Chenting Zhang ◽  
Haiyang Tang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Transient Receptor Potential ◽  
Muscle Cells ◽  
Transient Receptor Potential Channels ◽  
Nuclear Accumulation ◽  
Pulmonary Vascular Disease ◽  
Pulmonary Arterial

The tumor-suppressive role of p53, a transcription factor that regulates the expression of many genes, has been linked to cell cycle arrest, apoptosis, and senescence. The noncanonical function or the pathogenic role of p53 has more recently been implicated in pulmonary vascular disease. We previously reported that rapid nuclear accumulation of hypoxia-inducible factor (HIF)-1α in pulmonary arterial smooth muscle cells (PASMCs) upregulates transient receptor potential channels and enhances Ca2+ entry to increase cytosolic Ca2+ concentration ([Ca2+]cyt). Also, we observed differences in HIF-1α/2α expression in PASMCs and pulmonary arterial endothelial cells (PAECs). Here we report that p53 is increased in PAECs, but decreased in PASMCs, isolated from mice with hypoxia-induced pulmonary hypertension (PH) and rats with monocrotaline (MCT)-induced PH (MCT-PH). The increased p53 in PAECs from rats with MCT-PH is associated with an increased ratio of Bax/Bcl-2, while the decreased p53 in PASMCs is associated with an increased HIF-1α. Furthermore, p53 is downregulated in PASMCs isolated from patients with idiopathic pulmonary arterial hypertension compared with PASMCs from normal subjects. Overexpression of p53 in normal PASMCs inhibits store-operated Ca2+ entry (SOCE) induced by passive depletion of intracellularly stored Ca2+ in the sarcoplasmic reticulum, while downregulation of p53 enhances SOCE. These data indicate that differentially regulated expression of p53 and HIF-1α/2α in PASMCs and PAECs and the cross talk between p53 and HIF-1α/2α in PASMCs and PAECs may play an important role in the development of PH via, at least in part, induction of PAEC apoptosis and PASMC proliferation.

The unexpected role of PI3-kinase gamma in pulmonary hypertension

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
L Feik ◽  
E Berghausen ◽  
M Zierden ◽  
E Hirsch ◽  
S Baldus ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Specific Inhibitor ◽  
Left Ventricular ◽  
Brdu Incorporation ◽  
Pulmonary Vascular Disease ◽  
High Morbidity ◽  
Pulmonary Arterial ◽  
The Impact

Abstract Introduction Pulmonary hypertension (PH) is a pulmonary vascular disease that is associated with unacceptably high morbidity and mortality. PH is characterized by chronically increased pulmonary arterial pressure, increased pulmonary vascular resistance and right ventricular (RV) dysfunction and hypertrophy. Underlying mechanisms include increased proliferation and reduced apoptosis of both vascular smooth muscle cells (SMC) and endothelial cells (EC), as well as dysregulated immune responses. We have previously shown that class IA phosphatidylinositol-3-kinase (PI3K) isoforms, activated via receptor tyrosine kinases, are critically involved in the pathogenesis of PH. However, recent findings suggest that the class IB isoform PI3Kγ, which is activated downstream of G protein coupled receptors, is also important. It has been shown that PI3Kγ is involved in numerous processes that promote both vascular remodelling and maladaptive cardiac hypertrophy, including leukocyte recruitment, expression of proinflammatory chemokines and cytokines, as well as SMC and EC proliferation and survival. Therefore, the aim of our study was to investigate the role of PI3Kγ in the pathogenesis of PH. Methods The impact of PI3Kγ on the pathogenesis of PH was analysed in vivo using mice expressing a catalytically inactive form of PI3Kγ (PI3KγKD/KD) in the hypoxia-induced mouse model of PH. Mice were kept at 10%O2 (HOX) for 21 days or left under normoxic conditions (NOX). Subsequently, systolic right ventricular pressure (RVSP) was measured with a pressure catheter. RV hypertrophy was expressed as the ratio of RV weight to left ventricular + septum weight. Migration and proliferation of human pulmonary arterial SMC (hPASMC) as well as EC (hMVEC) were analysed using a PI3Kγ isoform-specific inhibitor (AS605240 [0.1; 0.3; 1μM]). Chemotaxis was determined by means of a modified Boyden chamber, and proliferation was quantified by a Bromodeoxyuridine (BrdU) incorporation assay. Results Whereas PI3Kγ inactivation had no effect on NOX animals, hypoxia led to increased RVSP and RV hypertrophy in WT animals (34.67±2.02 mmHg; 0.38±0.087) which were unexpectedly further increased in PI3KγKD/KD mice (37.67±1.3 mmHg, p=0.0104 vs. HOX WT; 0.47±0.06, p=0.0155 vs. HOX WT). Heart rate and systemic blood pressure remained unchanged. Inhibition of PI3Kγ by means of AS605240 did not affect proliferation of hPASMC and hMVEC, induced by multiple stimuli (FCS [10%], PDGF-BB [30ng/ml], or CXCL12 [100ng/ml], VEGF [50ng/ml]), respectively. However, FCS-induced migration of these cells was significantly reduced by AS605240 [0.3μM] (p<0.05). Conclusion Contrary to our expectations, the results show that kinase inactivation of PI3Kγ was not able to attenuate the pathogenesis of PH, but surprisingly led to a significant increase without critically changing cellular responses of SMC and EC. Therefore, our results indicate an unexpected protective effect of PI3Kγ on PH. Funding Acknowledgement Type of funding source: None

scholarly journals The Role of RNA m6A Methylation in the Regulation of Postnatal Hypoxia-induced Pulmonary Hypertension

2020 ◽  
Author(s):  
shanshan xu ◽  
Xuefeng Xu ◽  
Ziming Zhang ◽  
Lingling Yan ◽  
Liyan Zhang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Lung Development ◽  
Systolic Pressure ◽  
Weight Ratio ◽  
Pulmonary Vasculature ◽  
Pulmonary Vascular Disease ◽  
Adult Rats ◽  
The Impact

Abstract Background: Pulmonary hypertension (PH) is a complex pulmonary vascular disease characterized by an imbalance in vasoconstrictor/vasodilator signaling within the pulmonary vasculature. Recent evidence suggests that exposure to hypoxia early in life can cause alterations in the pulmonary vasculature and lead to the development of PH. However, the long-term impact of postnatal hypoxia on lung development and pulmonary function remains unknown. N6-methyladenosine (m6A) regulates gene expression and governs many important biological processes. However, the function of m6A in the development of PH remains poorly characterized. Thus, the purpose of this investigation was to test the two-fold hypothesis that 1) postnatal exposure to hypoxia would alter lung development leading to PH in adult rats, and 2) m6A modification would change in rats exposed to hypoxia, suggesting it plays a role in the development of PH.Methods: Forty male Sprague-Dawley rats were exposed to a hypoxic environment (FiO2: 12%) within 24 h after birth for 2 weeks. PH was defined as an increased right ventricular systolic pressure (RVSP) and pathologic changes of pulmonary vasculature measured by α-SMA immunohistochemical staining. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) was performed to analyze m6A modification changes in lung tissue between 2 and 9 weeks following exposure to postnatal hypoxia.Results: mean pulmonary arterial pressure, lung/body weight ratio, and the Fulton index was significantly greater in rats exposed to hypoxia when compared to control and the difference persisted into adulthood. m6A methyltransferase and demethylase proteins were significantly downregulated in postnatal hypoxia-induced PH. Distinct m6A modification peak-related genes differed between the two groups, and these genes were associated with lung development.Conclusions: Our results indicate postnatal hypoxia dysregulates lung development, leading to PH, and may have a long-term effect on adult rat lung development via the alterations in pulmonary vasculature function. METTL3, a m6A methyltransferase, was elevated in rats exposed to postnatal hypoxia in both the postnatal period and in adulthood, suggesting that it contributes to the development of PH following postnatal hypoxia. Our findings provide new insights into the impact of postnatal hypoxia and the role of m6A in the development of pulmonary vascular pathophysiology.

Gender and belief factors on attitude towards Social and Environmental Accounting (SEA)

2009 ◽  
Vol 6 (2) ◽  
pp. 51
Author(s):  
Salina Abdullah ◽  
Ern Chen Loo
Keyword(s):  
Natural Resources ◽  
Undergraduate Students ◽  
Environmental Issues ◽  
Environmental Accounting ◽  
Future Generations ◽  
Business And Society ◽  
Four Dimensions ◽  
Sustain Ability ◽  
The Relationship

Research on social and environmental accounting (SEA) has mainly concentrated on disclosure of SEA by corporate bodies, where investigations on ones attitude towards SEA are rarely discussed. SEA is a medium that develops relationships between business and society, community and nature. In addition, SEA involves a concept of sustain ability; where natural resources need to be sustained for the needs of future generations (Alhabshi et al., 2003). SEA also tries to recognise the role of accounting in sustainable development and the use of environmental resources. There are arguments that the young generations today are not fully aware of preserving these natural resources as well as handling social and environmental issues wisely. This perhaps link closely to their belief and cultural background. Hence, this paper examines the influence of gender and belief factors on the undergraduate students’ attitude towards SEA. Four dimensions of belief (fixed ability, quick learning, simple knowledge and certain knowledge) proposed by Schommer (2005) were adapted to analyse how belief factors have influence on their attitude towards SEA. An independent sample t-test was used to examine the relationship between gender and students’ attitude towards SEA. Spearmen’s correlation was employed to show the relationship between belief and attitude towards SEA. The results revealed that gender differences did not show influences on their attitude towards SEA. It was found that there is a significant relationship between belief and students’ attitude towards SEA. Students who believe on the importance of SEA tend to report positive attitude towards SEA. Perhaps findings of this study may provide some information on the SEA education and further be incorporated in the syllabus.

The role of arterio-venous fistula in formation of pulmonary hypertension in patients on renal replacement therapy. A Review

2019 ◽  
Vol 21 (1) ◽  
pp. 19-31
Author(s):  
R.T. Ishakov ◽  
◽  
E.M. Zeltyn-Abramov ◽  
N.G. Potheshkina ◽  
N.I. Belavina ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Renal Replacement Therapy ◽  
Replacement Therapy ◽  
Venous Fistula

Does a Ribosome Really Read? On the Cognitive Roots and Heuristic Value of Linguistic Metaphors in Molecular Genetics. Part 2

2020 ◽  
Vol 63 (2) ◽  
pp. 46-62
Author(s):  
Suren T. Zolyan
Keyword(s):  
Information Processing ◽  
Genetic Information ◽  
Formal Organization ◽  
Dual Nature ◽  
Reading Frame ◽  
The Core ◽  
Genetic Information Processing ◽  
Cognitive Frame ◽  
Effective Instrument

We discuss the role of linguistic metaphors as a cognitive frame for the understanding of genetic information processing. The essential similarity between language and genetic information processing has been recognized since the very beginning, and many prominent scholars have noted the possibility of considering genes and genomes as texts or languages. Most of the core terms in molecular biology are based on linguistic metaphors. The processing of genetic information is understood as some operations on text – writing, reading and editing and their specification (encoding/decoding, proofreading, transcription, translation, reading frame). The concept of gene reading can be traced from the archaic idea of the equation of Life and Nature with the Book. Thus, the genetics itself can be metaphorically represented as some operations on text (deciphering, understanding, code-breaking, transcribing, editing, etc.), which are performed by scientists. At the same time linguistic metaphors portrayed gene entities also as having the ability of reading. In the case of such “bio-reading” some essential features similar to the processes of human reading can be revealed: this is an ability to identify the biochemical sequences based on their function in an abstract system and distinguish between type and its contextual tokens of the same type. Metaphors seem to be an effective instrument for representation, as they make possible a two-dimensional description: biochemical by its experimental empirical results and textual based on the cognitive models of comprehension. In addition to their heuristic value, linguistic metaphors are based on the essential characteristics of genetic information derived from its dual nature: biochemical by its substance, textual (or quasi-textual) by its formal organization. It can be concluded that linguistic metaphors denoting biochemical objects and processes seem to be a method of description and explanation of these heterogeneous properties.

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