scholarly journals Protective effects of dioscin on vascular remodeling in pulmonary arterial hypertension via adjusting GRB2/ERK/PI3K-AKT signal

2021 ◽  
Vol 133 ◽  
pp. 111056
Author(s):  
Yueyue Yang ◽  
Lianhong Yin ◽  
Manning Zhu ◽  
Shasha Song ◽  
Changjie Sun ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Protective Effects ◽  
Pulmonary Arterial

scholarly journals Anti-Inflammatory Effect of Allicin Associated with Fibrosis in Pulmonary Arterial Hypertension

2021 ◽  
Vol 22 (16) ◽  
pp. 8600
Author(s):  
José L. Sánchez-Gloria ◽  
Constanza Estefanía Martínez-Olivares ◽  
Pedro Rojas-Morales ◽  
Rogelio Hernández-Pando ◽  
Roxana Carbó ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Wall Thickness ◽  
Vascular Remodeling ◽  
Protective Effects ◽  
Pulmonary Vascular Remodeling ◽  
Vessel Wall Thickness ◽  
Tnf Α ◽  
Male Wistar Rats ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling. Recent evidence supports that inflammation plays a key role in triggering and maintaining pulmonary vascular remodeling. Recent studies have shown that garlic extract has protective effects in PAH, but the precise role of allicin, a compound derived from garlic, is unknown. Thus, we used allicin to evaluate its effects on inflammation and fibrosis in PAH. Male Wistar rats were divided into three groups: control (CON), monocrotaline (60 mg/kg) (MCT), and MCT plus allicin (16 mg/kg/oral gavage) (MCT + A). Right ventricle (RV) hypertrophy and pulmonary arterial medial wall thickness were determined. IL-1β, IL-6, TNF-α, NFкB p65, Iкβ, TGF-β, and α-SMA were determined by Western blot analysis. In addition, TNF-α and TGF-β were determined by immunohistochemistry, and miR-21-5p and mRNA expressions of Cd68, Bmpr2, and Smad5 were determined by RT-qPCR. Results: Allicin prevented increases in vessel wall thickness due to TNF-α, IL-6, IL-1β, and Cd68 in the lung. In addition, TGF-β, α-SMA, and fibrosis were lower in the MCT + A group compared with the MCT group. In the RV, allicin prevented increases in TNF-α, IL-6, and TGF-b. These observations suggest that, through the modulation of proinflammatory and profibrotic markers in the lung and heart, allicin delays the progression of PAH.

Model Characterization of Pulmonary Arterial Hypertension: Analysis of Lung Pathology with Respect to Human Disease

2020 ◽  
Author(s):  
◽  
Eptisam lambu
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Human Disease ◽  
Vascular Remodeling ◽  
Vascular Wall ◽  
Lung Pathology ◽  
Pulmonary Arterial ◽  
Lung Pathogenesis ◽  
Arterial Endothelial Cells

Pulmonary arterial hypertension (PAH) is a rare multifactorial disease characterized by abnormal high blood pressure in the pulmonary artery, or increased pulmonary vascular resistance (PVR), caused by obstruction in the small arteries of the lung. Increased PVR is also thought to be caused by abnormal vascular remodeling, due to thickening of the pulmonary vascular wall resulting from significant hypertrophy of pulmonary arterial smooth-muscle cells (PASMCs) and increased proliferation/impaired apoptosis of pulmonary arterial endothelial cells (PAECs). Herein, we investigated the mechanisms and explored molecular pathways mediating the lung pathogenesis in two PAH rat models: Monocrotaline (MCT) and Sugen5416/Hypoxia (SuHx). We analyzed these disease models to determine where the vasculature shows the most severe PAH pathology and which model best recapitulates the human disease. We investigated the role vascular remodeling, hypoxia, cell proliferation, apoptosis, DNA damage and inflammation play in the pathogenesis of PAH. Neither model recapitulated all features of the human disease, however each model presented with some of the pathology seen in PAH patients.

scholarly journals Restoration of Vitamin D Levels Improves Endothelial Function and Increases TASK-Like K+ Currents in Pulmonary Arterial Hypertension Associated with Vitamin D Deficiency

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 795
Author(s):  
Maria Callejo ◽  
Daniel Morales-Cano ◽  
Gema Mondejar-Parreño ◽  
Bianca Barreira ◽  
Sergio Esquivel-Ruiz ◽  
...  
Keyword(s):  
Vitamin D ◽  
Pulmonary Arterial Hypertension ◽  
Endothelial Function ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Standard Diet ◽  
Pulmonary Vascular Remodeling ◽  
Vitamin D Levels ◽  
Pulmonary Arterial ◽  
K Currents

Background: Vitamin D (vitD) deficiency is highly prevalent in patients with pulmonary arterial hypertension (PAH). Moreover, PAH-patients with lower levels of vitD have worse prognosis. We hypothesize that recovering optimal levels of vitD in an animal model of PAH previously depleted of vitD improves the hemodynamics, the endothelial dysfunction and the ionic remodeling. Methods: Male Wistar rats were fed a vitD-free diet for five weeks and then received a single dose of Su5416 (20 mg/Kg) and were exposed to vitD-free diet and chronic hypoxia (10% O2) for three weeks to induce PAH. Following this, vitD deficient rats with PAH were housed in room air and randomly divided into two groups: (a) continued on vitD-free diet or (b) received an oral dose of 100,000 IU/Kg of vitD plus standard diet for three weeks. Hemodynamics, pulmonary vascular remodeling, pulmonary arterial contractility, and K+ currents were analyzed. Results: Recovering optimal levels of vitD improved endothelial function, measured by an increase in the endothelium-dependent vasodilator response to acetylcholine. It also increased the activity of TASK-1 potassium channels. However, vitD supplementation did not reduce pulmonary pressure and did not ameliorate pulmonary vascular remodeling and right ventricle hypertrophy. Conclusions: Altogether, these data suggest that in animals with PAH and severe deficit of vitD, restoring vitD levels to an optimal range partially improves some pathophysiological features of PAH.

scholarly journals AB1139 DIAGNOSTICIS AND PROGNOSTICIS SIGNIFICANCE OF CHEST CT EVALUATION OF SMALL PULMONARY VESSELS IN CONNECTIVE TISSUE DISEASES WITH PULMONARY ARTERIAL HYPERTENSION.

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1859.1-1860
Author(s):  
Y. Zhang ◽  
N. Zhang ◽  
Y. Zhu ◽  
Q. Wang ◽  
L. Zhou
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Connective Tissue ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Connective Tissue Diseases ◽  
Chest Ct ◽  
Pulmonary Vessels ◽  
Ct Evaluation ◽  
Pulmonary Arterial

Background:Pulmonary arterial hypertension (PAH) is a fatal complication of connective tissue diseases (CTDs). Chest CT has been increasingly used in the evaluation of patients with suspected PH noninvasively but there is a paucity of studies.Objectives:Our study was aimed to investigate the cross-sectional area (CSA) of small pulmonary vessels on chest CT for the diagnosis and prognosis of CTD-PAH.Methods:This retrospective study analyzed the data of thirty-four patients with CTD-PAH who were diagnosed by right heart catheterization (RHC) and underwent chest CT between March 2011 and October 2019. We measured the percentage of total CSA of vessels<5 mm2and 5-10 mm2as a percentage of total lung area (%CSA<5and %CSA5-10) on Chest CT. Furthermore, the association of %CSA with mean pulmonary artery pressure (mPAP) was also investigated. Besides, these patients were followed up until October 2019, and Kaplan-Meier survival curves were generated for the evaluation of prognosis.Results:Patients with CTD-PAH had significantly higher %CSA5-10than CTD-nPAH (p=0.001), %CSA5-10in CTD-S-PAH and IPAH was significantly higher than CTD-LM-PAH and COPD-PH (p<0.01). There was a positive correlation between %CSA5-10and mPAP in CTD-PAH (r=0.447, p=0.008). Considering %CSA5-10above 0.38 as a threshold level, the sensitivity and specificity were found to be 0.824 and 0.706, respectively. Patients with %CSA5-10≥0.38 had a lower survival rate than those with %CSA5-10<0.38 (p=0.049).Conclusion:Quantitative parameter, %CSA5-10on Chest CT might serve a crucial differential diagnostic tool for different types of PH. %CSA5-10≥0.38 is a prognostic indicator for evaluation of CTD-PAH.References:[1]Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension. Rev Esp Cardiol (Engl Ed). 2016;69(2):177.[2]Siddiqui I, Rajagopal S, Brucker A, et al. Clinical and Echocardiographic Predictors of Outcomes in Patients With Pulmonary Hypertension. Am J Cardiol. 2018;122(5):872-878.[3]Coste F, Dournes G, Dromer C, et al. CT evaluation of small pulmonary vessels area in patients with COPD with severe pulmonary hypertension. Thorax. 2016;71(9):830-837.[4]Freed BH, Collins JD, Francois CJ, et al. MR and CT Imaging for the Evaluation of Pulmonary Hypertension. JACC Cardiovasc Imaging. 2016;9(6):715-732.[5]Pietra GG, Capron F, Stewart S, et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):25S-32S.[6]Zanatta E, Polito P, Famoso G, et al. Pulmonary arterial hypertension in connective tissue disorders: Pathophysiology and treatment. Exp Biol Med (Maywood). 2019;244(2):120-131.[7]Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014;115(1):165-175.[8]Thenappan T, Ormiston ML, Ryan JJ, Archer SL. Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ. 2018;360:j5492.[9]Thompson AAR, Lawrie A. Targeting Vascular Remodeling to Treat Pulmonary Arterial Hypertension. Trends Mol Med. 2017;23(1):31-45.[10]Shimoda LA, Laurie SS. Vascular remodeling in pulmonary hypertension. J Mol Med (Berl). 2013;91(3):297-309.[11]Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest. 2012;122(12):4306-4313.[12]Seeger W, Adir Y, Barbera JA, et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol. 2013;62(25 Suppl):D109-116.Acknowledgments:Thanks to all patients involved in this retrospective study. Thanks go to every participant who participated in this study for their enduring efforts in working with participants to complete the study. Thanks to Liangmin Wei for helping us with statistics analysis.Disclosure of Interests:None declared

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.

Abstract 18446: Identification of a Novel Cellular Actor Participating in Vascular Remodeling During Pulmonary Arterial Hypertension : the PW1+ Progenitor Cells

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
France Dierick
Keyword(s):  
Bone Marrow ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Bone Marrow Cells ◽  
Mouse Lung ◽  
Pulmonary Vessels ◽  
Pulmonary Arterial ◽  
Lung Vessels

AIM: PW1+ progenitors were identified in various adult tissues and can differentiate in smooth muscle cells (SMC) in vitro. Our hypothesis is that PW1+ progenitors are recruited to participate in the vascular remodeling during pulmonary arterial hypertension (PAH). METHODS: PW1IRESnLacZ+/- mice express the β-galactosidase as a reporter gene for PW1 expression allowing to follow the lineage of PW1+ cells during a few days. These mice were exposed to chronic hypoxia (CH) to induce PAH, lung vessels neomuscularisation and SMC proliferation. PW1+ and β-Gal+ cells were studied by FACS and by immunofluorescence. RESULTS: PW1+ cells are localized in the lung parenchyma and in the perivascular zone in rodent and human lung. Two PW1+ populations were identified by flow cytometry in the mouse lung 1/ a Sca-1high/CD34high/PDGFR-α+ population which differentiates into calponin+ or α-SMA+ SMC and into vWF+ endothelial cell and 2/ a CD34-/CD146+ population expressing pericyte markers. After 2-4 days of CH, the number of lung PW1+ cells is increased (x3.5, p<0.01) and, in small pulmonary vessels media, the proportion of β-Gal+ SMC derived from PW1+ cells is increased (64±6% vs 35±3%, p<0.05) suggesting a recruitment and differentiation of PW1+ cells into lung vascular SMC. Moreover WT mice irradiated and engrafted with GFP+/β-Gal+ bone marrow cells do not show any increase in GFP+ SMC in lung vessels and do not show any β-Gal+ cells in the lung indicating that the lung PW1+ progenitors are not derived from bone marrow . Moreover, in the human PAH lung, PW1+ cells were observed in remodeled vascular structures: in the media of remodeled vessel and in plexiform lesions. CONCLUSION: These results suggest that lung resident PW1+ progenitors are recruited to participate in the vascular remodeling of small pulmonary vessels in experimental and human PAH. These progenitors show characteristics of pericytes and of vascular progenitors.

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