NSD2 silencing alleviates pulmonary arterial hypertension by inhibiting trehalose metabolism and autophagy

2019 ◽  
Vol 133 (9) ◽  
pp. 1085-1096 ◽  
Author(s):  
Xue-liang Zhou ◽  
Zhi-bo Liu ◽  
Rong-rong Zhu ◽  
Huang Huang ◽  
Qi-rong Xu ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Lung Tissue ◽  
Metabolic Reprogramming ◽  
Mineral Absorption ◽  
Right Ventricle Dysfunction ◽  
Trehalose Metabolism ◽  
Pulmonary Arterial

Abstract Nuclear receptor binding SET domain 2 (NSD2)-mediated metabolic reprogramming has been demonstrated to regulate oncogenesis via catalyzing the methylation of histones. The present study aimed to investigate the role of NSD2-mediated metabolic abnormality in pulmonary arterial hypertension (PAH). Monocrotaline (MCT)-induced PAH rat model was established and infected with adeno-associated virus carrying short hairpin RNA (shRNA) targeting NSD2. Hemodynamic parameters, ventricular function, and pathology were evaluated by microcatheter, echocardiography, and histological analysis. Metabolomics changes in lung tissue were analyzed by LC–MS. The results showed that silencing of NSD2 effectively ameliorated MCT-induced PAH and right ventricle dysfunction, and partially reversed pathological remodeling of pulmonary artery and right ventricular hypertrophy. In addition, the silencing of NSD2 markedly reduced the di-methylation level of H3K36 (H3K36me2 level) and inhibited autophagy in pulmonary artery. Non-targeted LC–MS based metabolomics analysis indicated that trehalose showed the most significant change in lung tissue. NSD2-regulated trehalose mainly affected ABC transporters, mineral absorption, protein digestion and absorption, metabolic pathways, and aminoacyl-tRNA biosynthesis. In conclusion, we reveal a new role of NSD2 in the pathogenesis of PAH related to the regulation of trehalose metabolism and autophagy via increasing the H3K36me2 level. NSD2 is a promising target for PAH therapy.

ID: 123: ROLE OF MICRORNA-1 IN REGULATING PULMONARY VASCULAR REMODELING IN PULMONARY ARTERIAL HYPERTENSION

2016 ◽  
Vol 64 (4) ◽  
pp. 969.1-969 ◽  
Author(s):  
JR Sysol ◽  
J Chen ◽  
S Singla ◽  
V Natarajan ◽  
RF Machado ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Luciferase Reporter ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle

RationalePulmonary arterial hypertension (PAH) is a severe, progressive disease characterized by increased pulmonary arterial pressure and resistance due in part to uncontrolled vascular remodeling. The mechanisms contributing to vascular remodeling in PAH are poorly understood and involve rampant pulmonary artery smooth muscle cell (PASMC) proliferation. We recently demonstrated the important role of sphingosine kinase 1 (SphK1), a lipid kinase producing pro-proliferative sphingosine-1-phosphate (S1P), in the development of pulmonary vascular remodeling in PAH. However, the regulatory processes involved in upregulation of SphK1 in this disease are unknown.ObjectiveIn this study, we aimed to identify novel molecular mechanisms governing the regulation of SphK1 expression, with a focus on microRNA (miR). Using both in vitro studies in pulmonary artery smooth muscle cells (PASMCs) and an in vivo mouse model of experimental hypoxia-mediated pulmonary hypertension (HPH), we explored the role of miR in controlling SphK1 expression in the development of pulmonary vascular remodeling.Methods and ResultsIn silico analysis identified hsa-miR-1-3p (miR-1) as a candidate targeting SphK1. We demonstrate miR-1 is down-regulated by hypoxia in human PASMCs and in lung tissues of mice with HPH, coinciding with upregulation of SphK1 expression. PASMCs isolated from patients with PAH had significantly reduced expression of miR-1. Transfection of human PASMCs with miR-1 mimics significantly attenuated activity of a SphK1-3'-UTR luciferase reporter construct and SphK1 protein expression. miR-1 overexpression in human PASMCs also inhibited proliferation and migration under normoxic and hypoxic conditions, both important in pathogenic vascular remodeling in PAH. Finally, we demonstrated that intravenous administration of miR-1 mimics prevents the development of experimental HPH in mice and attenuates induction of SphK1 in PASMCs.ConclusionThese data demonstrate that miR-1 expression in reduced in PASMCs from PAH patients, is modulated by hypoxia, and regulates the expression of SphK1. Key phenotypic aspects of vascular remodeling are influenced by miR-1 and its overexpression can prevent the development of HPH in mice. These studies further our understanding of the mechanisms underlying pathogenic pulmonary vascular remodeling in PAH and could lead to novel therapeutic targets.Supported by grants NIH/NHLBI R01 HL127342 and R01 HL111656 to RFM, NIH/NHLBI P01 HL98050 and R01 HL127342 to VN, American Heart Association Predoctoral Fellowship (15PRE2190004) to JRS, and NIH/NLHBI NRSA F30 Fellowship (FHL128034A) to JRS.

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.

scholarly journals EXPRESS: Phosphoproteomic Analysis of Lung tissue from Patients with Pulmonary Arterial Hypertension

2021 ◽  
pp. 204589402110311
Author(s):  
Ravikumar Sitapara ◽  
Tukiet Lam ◽  
Aneta Gandjeva ◽  
Rubin Tuder ◽  
Lawrence Zisman
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Lung Tissue ◽  
Immune Regulation ◽  
Potential Role ◽  
Rho Gtpase ◽  
High Morbidity ◽  
Pulmonary Arterial

Pulmonary Arterial Hypertension (PAH) is a rare disorder associated with high morbidity and mortality despite currently available treatments. We compared the phosphoproteome of lung tissue from subjects with iPAH obtained at the time of lung transplant with control lung tissue. The mass spectrometry-based analysis found 60,428 phosphopeptide features from which 6622 proteins were identified. Within the subset of identified proteins there were 1234 phosphopeptides with q<0.05, many of which are involved in immune regulation, angiogenesis, and cell proliferation. Most notably there was a marked relative increase in phosphorylated (S378) IKZF3 (Aiolos), a zinc finger transcription factor that plays a key role in lymphocyte regulation. In vitro phosphorylation assays indicated that GSK3 alpha and/or GSK3 beta could phosphorylate IKZF3 at S378. Western blot analysis demonstrated increased pIKZF3 in iPAH lungs compared to controls. Immunohistochemistry demonstrated phosphorylated IKZF3 in lymphocytes surrounding severely hypertrophied pulmonary arterioles. In situ hybrization showed gene expression in lymphocyte aggregates in PAH samples. A BCL2 reporter assay showed that IKZF3 increased BCL2 promoter activity and demonstrated the potential role of phosphorylation of IKZF3 on the regulation of BCL mediated transcription. Kinase network analysis demonstrated potentially important regulatory roles of casein kinase 2, CDK1, MAPKs, and PRKs in iPAH. Bioinformatic analysis demonstrated enrichment of Rho GTPase signaling and the potential importance of PRKG. In conclusion, this unbiased phosphoproteomic analysis demonstrated several novel targets regulated by kinase networks in iPAH, and reinforced the potential role of immune regulation in the pathogenesis of iPAH. The identified up and down-regulated phosphoproteins have potential to serve as biomarkers for PAH and to provide new insights for therapeutic strategies.

Navigating the Road to Transplant in Pulmonary Arterial Hypertension: A Road Less Taken

2016 ◽  
Vol 15 (1) ◽  
pp. 12-13
Author(s):  
Adaani E. Frost ◽  
Harrison W. Farber
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Lung Transplantation ◽  
Small Cell ◽  
Small Cell Lung ◽  
Donor Organ ◽  
The Road ◽  
Lung Allocation Score ◽  
Pulmonary Arterial

Dramatic advances in therapy for pulmonary arterial hypertension (PAH) in the last 20 years have improved survival from a median of 2.5 years in the pretreatment era to 7.5 years currently. However, impressive as that may seem, it is important to note that a median survival of 7.5 years is equivalent to that of surgically resected non-small cell lung cancer, thus underscoring the importance of lung transplantation as a treatment option in patients with PAH. In this edition of Advances, Edelman has reviewed the pathway to transplantation for patients with PAH, detailing the recommendations for timing of referral, listing for lung transplantation, the role of the lung allocation score in allocating a donor organ, and the outcome of lung transplantation.

An Expanding Role of Biomarkers in Pulmonary Arterial Hypertension

2017 ◽  
Vol 18 (6) ◽  
Author(s):  
Mustafa Yildiz ◽  
Alparslan Sahin ◽  
Michael Behnes ◽  
İbrahim Akin
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Pulmonary Arterial

scholarly journals Prognostic impact of neurohormonal inhibition in pulmonary arterial hypertension

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R Scagliola ◽  
I Rota ◽  
M Cheli ◽  
C Brunelli ◽  
M Balbi ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Beta Blocker ◽  
Diastolic Pressure ◽  
Smoking Habit ◽  
Prognostic Impact ◽  
Mineralocorticoid Receptor Antagonist ◽  
Kaplan Meier ◽  
Pulmonary Arterial

Abstract Background Experimental evidence points towards a hyperactivity of the sympathetic nervous system and renin-angiotensin-aldosterone system in the pathobiology of pulmonary arterial hypertension (PAH), raising the hypothesis that blockade of neurohormonal axis may have favorable effects in this context. Purpose To assess the use and prognostic impact of neurohormonal inhibitors (NEUi) in a single centre cohort of subjects with PAH. Methods We analysed retrospectively collected data from our register of right heart catheterizations (RHC) performed consecutively from January 1st 2005 until October 31st 2018. We selected patients with PAH and complete information about demographics, biochemical data and drug therapy at the time of RHC. Patients on beta-blocker, angiotensin-converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB) or mineralocorticoid receptor antagonist (MRA) at the time of RHC were classified as NEUi users. Comparisons between NEUi recipients and non-recipients were drawn by chi-square or t-test, as appropriate. Death from any cause was assessed by Kaplan-Meier analysis. Results Complete data were available for 57 PAH patients. Mean pulmonary artery pressure, pulmonary artery wedge pressure, diastolic pressure gradient, pulmonary vascular resistance and cardiac index were 45.0±14.9 mmHg, 10.9±3.5 mmHg, 16.0±10.2 mmHg, 8.8±5.1 Wood units and 2.5±0.8 l/min/m2 respectively. Twenty-seven subjects (47.4%) were taking at least one NEUi when RHC was performed: 12 (21.1%) were on beta-blocker, 15 (26.3%) on ACEi/ARB and 6 (10.5%) on MRA. NEUi users were significantly older (67.6±11.9 vs. 58.3±15.2 years, p=0.039), had a higher body mass index (25.9±4.4 vs. 23.6±3.5, p=0.029), more frequently systemic arterial hypertension (74.1% vs. 40.0%, p=0.020), smoking habit (51.9% vs. 20.0%, p=0.025) and lower estimated glomerular filtration rate (58.7±22.7 vs. 73.7±24.7 ml/min/1.73 m2, p=0.022) than non-users. Moreover, 5 NEUi users (18.5%), but no NEUi non-users, had a history of coronary artery disease. Hemodynamic parameters were similar in NEUi recipients and non-recipients (p=NS). Seven patients (25.9%) died in the NEUi users group vs. 17 (56.7%) in the non-users one (p=0.038). Kaplan-Meier analysis confirmed that subjects not taking NEUi were more likely to die over the course of follow-up (Log-Rank p=0.020) (Figure 1). Conclusions Our data identify a subset of atypical PAH patients, with pre-capillary pulmonary hypertension and a comorbidity profile for left heart disease (LHD), in whom NEUi have shown to improve survival. A prognostic benefit of NEUi, due to their effects on cardiovascular comorbidities in this kind of patients, has been speculated. Future prospective studies are needed to identify the most appropriate treatment strategies for atypical forms of PAH, with subtle and probably covert LHD. Figure 1. Kaplan-Meier survival curves Funding Acknowledgement Type of funding source: None

Sign in / Sign up

Export Citation Format

Share Document