scholarly journals Pathobiology of pulmonary artery hypertension: role of long non-coding RNAs

2020 ◽  
Vol 116 (12) ◽  
pp. 1937-1947 ◽  
Author(s):  
Kashif Rafiq Zahid ◽  
Umar Raza ◽  
Jidong Chen ◽  
Usha J Raj ◽  
Deming Gou
Keyword(s):  
Pulmonary Artery ◽  
Right Ventricular Dysfunction ◽  
Pulmonary Artery Hypertension ◽  
Endothelial Cell Proliferation ◽  
Vascular Remodelling ◽  
Mesenchymal Transition ◽  
Pulmonary Arterial ◽  
Non Coding Rnas

Abstract Pulmonary arterial hypertension (PAH) is a disease with complex pathobiology, significant morbidity and mortality, and remains without a cure. It is characterized by vascular remodelling associated with uncontrolled proliferation of pulmonary artery smooth muscle cells, endothelial cell proliferation and dysfunction, and endothelial-to-mesenchymal transition, leading to narrowing of the vascular lumen, increased vascular resistance and pulmonary arterial pressure, which inevitably results in right heart failure and death. There are multiple molecules and signalling pathways that are involved in the vascular remodelling, including non-coding RNAs, i.e. microRNAs and long non-coding RNAs (lncRNAs). It is only in recent years that the role of lncRNAs in the pathobiology of pulmonary vascular remodelling and right ventricular dysfunction is being vigorously investigated. In this review, we have summarized the current state of knowledge about the role of lncRNAs as key drivers and gatekeepers in regulating major cellular and molecular trafficking involved in the pathogenesis of PAH. In addition, we have discussed the limitations and challenges in translating lncRNA research in vivo and in therapeutic applications of lncRNAs in PAH.

Effects of Estrogen on Pulmonary Vascular Remodeling in Pulmonary Artery Hypertension

2013 ◽  
Author(s):  
Aiping Liu ◽  
Naomi Chesler
Keyword(s):  
Pulmonary Artery ◽  
Progressive Increase ◽  
Pulmonary Artery Hypertension ◽  
Pulmonary Vascular Remodeling ◽  
Vegf Inhibitor ◽  
Vascular Impedance ◽  
Pulmonary Arterial ◽  
The Relationship

Pulmonary artery hypertension (PAH) is a female dominant, fatal disease characterized by progressive increase of pulmonary vascular resistance and loss of compliance. The role of estrogen in these pulmonary vascular changes with PAH progression remains unclear. Our objective was to study the effects of estrogen on pulmonary arterial (PA) remodeling in a mouse model of progressive PAH, created via a combination of a VEGF inhibitor Sugen and chronic hypoxia (SuHx). To quantify PA hemodynamics, we measured in vivo pressure and flow simultaneously in live mice in order to obtain pulmonary vascular impedance, a comprehensive measure of RV afterload. Our results demonstrate that estrogen modifies the relationship between PA resistance and compliance by attenuating PA stiffening, which provides insight into sex differences in PAH progression.

scholarly journals Role of Long Non-Coding RNAs in Pulmonary Arterial Hypertension

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1892
Author(s):  
Yun Han ◽  
Md Khadem Ali ◽  
Kamal Dua ◽  
Edda Spiekerkoetter ◽  
Yuqiang Mao
Keyword(s):  
Cell Proliferation ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Phenotypic Switching ◽  
Endothelial Cell Proliferation ◽  
Mesenchymal Transition ◽  
Potential Biomarker ◽  
Pulmonary Arterial ◽  
Non Coding Rnas

Pulmonary arterial hypertension (PAH) is a debilitating condition of the pulmonary circulatory system that occurs in patients of all ages and if untreated, eventually leads to right heart failure and death. Despite existing medical treatment options that improve survival and quality of life, the disease remains incurable. Thus, there is an urgent need to develop novel therapies to treat this disease. Emerging evidence suggests that long non-coding RNAs (lncRNAs) play critical roles in pulmonary vascular remodeling and PAH. LncRNAs are implicated in pulmonary arterial endothelial dysfunction by modulating endothelial cell proliferation, angiogenesis, endothelial mesenchymal transition, and metabolism. LncRNAs are also involved in inducing different pulmonary arterial vascular smooth muscle cell phenotypes, such as cell proliferation, apoptosis, migration, regulation of the phenotypic switching, and cell cycle. LncRNAs are essential regulators of gene expression that affect various diseases at the chromatin, transcriptional, post-translational, and even post-translational levels. Here, we focus on the role of LncRNAs and their molecular mechanisms in the pathogenesis of PAH. We also discuss the current research challenge and potential biomarker and therapeutic potentials of lncRNAs in PAH.

scholarly journals Epigenetic Regulation of Endothelial Dysfunction and Inflammation in Pulmonary Arterial Hypertension

2021 ◽  
Vol 22 (22) ◽  
pp. 12098
Author(s):  
Jaylen Hudson ◽  
Laszlo Farkas
Keyword(s):  
Endothelial Dysfunction ◽  
Pulmonary Artery Hypertension ◽  
Metabolic Reprogramming ◽  
Pulmonary Vascular Disease ◽  
Epigenetic Changes ◽  
Apoptosis Resistance ◽  
Cell Dysfunction ◽  
Pulmonary Arterial ◽  
Non Coding Rnas

Once perceived as a disorder treated by vasodilation, pulmonary artery hypertension (PAH) has emerged as a pulmonary vascular disease with severe endothelial cell dysfunction. In the absence of a cure, many studies seek to understand the detailed mechanisms of EC regulation to potentially create more therapeutic options for PAH. Endothelial dysfunction is characterized by complex phenotypic changes including unchecked proliferation, apoptosis-resistance, enhanced inflammatory signaling and metabolic reprogramming. Recent studies have highlighted the role of epigenetic modifications leading to pro-inflammatory response pathways, endothelial dysfunction, and the progression of PAH. This review summarizes the existing literature on epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs, which can lead to aberrant endothelial function. Our goal is to develop a conceptual framework for immune dysregulation and epigenetic changes in endothelial cells in the context of PAH. These studies as well as others may lead to advances in therapeutics to treat this devastating disease.

Sex Differences in Right Ventricular-Vascular Coupling and Pulmonary Artery Impedance in Response to Chronic Hypoxia and Recovery

2012 ◽  
Author(s):  
Aiping Liu ◽  
Lian Tian ◽  
Diana M. Tabima ◽  
Naomi C. Chesler
Keyword(s):  
Pulmonary Artery ◽  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Pulmonary Artery Hypertension ◽  
Vascular Impedance ◽  
Female Predominance ◽  
Collagen Accumulation ◽  
Dominant Disease ◽  
Pulmonary Arterial

Pulmonary artery hypertension (PAH) is a female dominant disease (the female-to-male ratio is 4:1), characterized by small distal pulmonary arterial narrowing and large proximal arterial stiffening, which increase right ventricle (RV) afterload and ultimately lead to RV failure [1,2]. Our recent studies have shown that collagen accumulation induced by chronic hypoxia increases the stiffness of the large extralobar pulmonary arteries (PAs) [3], and affects pulmonary vascular impedance (PVZ) [4]. The role of collagen in the female predominance in developing PAH has not been explored to date.

scholarly journals Notch3 signalling and vascular remodelling in pulmonary arterial hypertension

2019 ◽  
Vol 133 (24) ◽  
pp. 2481-2498 ◽  
Author(s):  
Hannah E. Morris ◽  
Karla B. Neves ◽  
Augusto C. Montezano ◽  
Margaret R. MacLean ◽  
Rhian M. Touyz
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Vascular Remodelling ◽  
Cellular Processes ◽  
Vascular Morphogenesis ◽  
Development And Differentiation ◽  
Pulmonary Arterial ◽  
And Function

Abstract Notch signalling is critically involved in vascular morphogenesis and function. Four Notch isoforms (Notch1–4) regulating diverse cellular processes have been identified. Of these, Notch3 is expressed almost exclusively in vascular smooth muscle cells (VSMCs), where it is critically involved in vascular development and differentiation. Under pathological conditions, Notch3 regulates VSMC switching between the contractile and synthetic phenotypes. Abnormal Notch3 signalling plays an important role in vascular remodelling, a hallmark of several cardiovascular diseases, including pulmonary arterial hypertension (PAH). Because of the importance of Notch3 in VSMC (de)differentiation, Notch3 has been implicated in the pathophysiology of pulmonary vascular remodelling in PAH. Here we review the current literature on the role of Notch in VSMC function with a focus on Notch3 signalling in pulmonary artery VSMCs, and discuss potential implications in pulmonary artery remodelling in PAH.

Downregulation of long noncoding RNA T1NCR inhibits cell proliferation, invasion, and epithelial-mesenchymal transition of hepatocellular carcinoma

2021 ◽  
Vol 7 (6) ◽  
pp. 6499-6510
Author(s):  
Hongjuan Li ◽  
Yaqin Chen ◽  
Chunyan Wu ◽  
Haiyan Zhao ◽  
Xuesong Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Noncoding Rna ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Normal Tissues ◽  
Proliferation Ability ◽  
Non Coding Rnas

Accumulating reports have identified that long non-coding RNAs (IncRNAs) function as key regulators of tumor initiation and progression. The aim of the current study was to determine the clinical significance and functional role of TINCR in hepatocellular carcinoma (HCC). In the present study, the level of IncRNA TINCR expression was significantly upregulated in HCC tissues compared to adjacent normal tissues. Higher levels of IncRNA TINCR expression were significantly correlated with tumor size and vascular invasion of HCC patients. LncRNA TINCR knockdown inhibited cell proliferation ability, increased the proportion of G1 phase cells, reduced the proportion of S phase cells, and suppressed cell invasion of HCC in vitro. Additionally, IncRNA TINCR knockdown inhibited the HCC cell epithelial-mesenchymal transition (EMT) phenomenon by upregulating E-cadherin and reducing N-cadherin expression. We demonstrated that knockdown of IncRNA reduced tumor growth in vivo. Thus, these results indicated that IncRNA TINCR exhibits a tumor oncogenic role in HCC and inhibition of IncRNA TINCR might serve as a therapeutic target for HCC.

scholarly journals Emerging Role of Galectin-3 in Pulmonary Artery Hypertension

2018 ◽  
Vol 1 (1) ◽  
pp. p35
Author(s):  
Alexander E. Berezin
Keyword(s):  
Heart Failure ◽  
Cell Proliferation ◽  
Pulmonary Artery ◽  
Short Communication ◽  
Clinical Status ◽  
Pulmonary Artery Hypertension ◽  
All Cause Mortality ◽  
Galectin 3 ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is multifactorial disadptive disease with poor clinical outcomes associated with increased pulmonary artery pressure resulting in primary small-to-moderate pulmonary artery remodeling. Numerous factors, including smooth muscle cell proliferation, vasospasm, vascular fibrosis and occlusion, direct vascular injury and inflammation, impaired repair of vasculature, are involved in the pathogenesis of PAH. It has been suggested that galectin-3 as a biomarker of excessive fibrosis and inflammation can be useful predictor of both severity and prognosis in patient with PAH. The short communication is reported that elevated Gal-3 levels were found in majority patients with PAH depending on clinical status and of the disease. Although elevated Gal-3 levels were associated with a higher risk of all-cause mortality, cardiovascular mortality, and right ventricle heart failure, the value of this biomarker in PAH patients at high risk stratification is uncertain and requires to be investigated in large clinical trials.

Magnesium Chloride is an Effective Therapeutic Agent for Prostate Cancer

2018 ◽  
Vol 8 (1) ◽  
pp. 62 ◽  
Author(s):  
Julianna Maria Santos ◽  
Fazle Hussain
Keyword(s):  
Prostate Cancer ◽  
Magnesium Chloride ◽  
Epithelial Mesenchymal Transition ◽  
Chromatin Condensation ◽  
Myosin Ii ◽  
In Vivo Studies ◽  
Migration Speed ◽  
Mesenchymal Transition

Background: Reduced levels of magnesium can cause several diseases and increase cancer risk. Motivated by magnesium chloride’s (MgCl2) non-toxicity, physiological importance, and beneficial clinical applications, we studied its action mechanism and possible mechanical, molecular, and physiological effects in prostate cancer with different metastatic potentials.Methods: We examined the effects of MgCl2, after 24 and 48 hours, on apoptosis, cell migration, expression of epithelial mesenchymal transition (EMT) markers, and V-H+-ATPase, myosin II (NMII) and the transcription factor NF Kappa B (NFkB) expressions.Results: MgCl2 induces apoptosis, and significantly decreases migration speed in cancer cells with different metastatic potentials.  MgCl2 reduces the expression of V-H+-ATPase and myosin II that facilitates invasion and metastasis, suppresses the expression of vimentin and increases expression of E-cadherin, suggesting a role of MgCl2 in reversing the EMT. MgCl2 also significantly increases the chromatin condensation and decreases NFkB expression.Conclusions: These results suggest a promising preventive and therapeutic role of MgCl2 for prostate cancer. Further studies should explore extending MgCl2 therapy to in vivo studies and other cancer types.Keywords: Magnesium chloride, prostate cancer, migration speed, V-H+-ATPase, and EMT.

scholarly journals Phosphorylation of Serine 11 and Serine 92 as New Positive Regulators of Human Snail1 Function: Potential Involvement of Casein Kinase-2 and the cAMP-activated Kinase Protein Kinase A

2010 ◽  
Vol 21 (2) ◽  
pp. 244-253 ◽  
Author(s):  
Matthew Reid MacPherson ◽  
Patricia Molina ◽  
Serhiy Souchelnytskyi ◽  
Christer Wernstedt ◽  
Jorge Martin-Pérez ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Tumor Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Cop9 Signalosome ◽  
Mesenchymal Transition ◽  
Depth Analysis ◽  
Positive Regulators

Snail1 is a major factor for epithelial-mesenchymal transition (EMT), an important event in tumor metastasis and in other pathologies. Snail1 is tightly regulated at transcriptional and posttranscriptional levels. Control of Snail1 protein stability and nuclear export by GSK3β phosphorylation is important for Snail1 functionality. Stabilization mechanisms independent of GSK3β have also been reported, including interaction with LOXL2 or regulation of the COP9 signalosome by inflammatory signals. To get further insights into the role of Snail1 phosphorylation, we have performed an in-depth analysis of in vivo human Snail1 phosphorylation combined with mutational studies. We identify new phosphorylation sites at serines 11, 82, and 92 and confirmed previously suggested phosphorylations at serine 104 and 107. Serines 11 and 92 participate in the control of Snail1 stability and positively regulate Snail1 repressive function and its interaction with mSin3A corepressor. Furthermore, serines 11 and 92 are required for Snail1-mediated EMT and cell viability, respectively. PKA and CK2 have been characterized as the main kinases responsible for in vitro Snail1 phosphorylation at serine 11 and 92, respectively. These results highlight serines 11 and 92 as new players in Snail1 regulation and suggest the participation of CK2 and PKA in the modulation of Snail1 functionality.

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