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 Epigenetic Targets for Oligonucleotide Therapies of Pulmonary Arterial Hypertension

2020 ◽  
Vol 21 (23) ◽  
pp. 9222
Author(s):  
William Gerthoffer
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Small Molecules ◽  
Vascular Remodeling ◽  
Arterial Wall ◽  
Vascular Wall ◽  
Wall Structure ◽  
Wall Thickening ◽  
Pulmonary Arterial

Arterial wall remodeling underlies increased pulmonary vascular resistance and right heart failure in pulmonary arterial hypertension (PAH). None of the established vasodilator drug therapies for PAH prevents or reverse established arterial wall thickening, stiffening, and hypercontractility. Therefore, new approaches are needed to achieve long-acting prevention and reversal of occlusive pulmonary vascular remodeling. Several promising new drug classes are emerging from a better understanding of pulmonary vascular gene expression programs. In this review, potential epigenetic targets for small molecules and oligonucleotides will be described. Most are in preclinical studies aimed at modifying the growth of vascular wall cells in vitro or normalizing vascular remodeling in PAH animal models. Initial success with lung-directed delivery of oligonucleotides targeting microRNAs suggests other epigenetic mechanisms might also be suitable drug targets. Those targets include DNA methylation, proteins of the chromatin remodeling machinery, and long noncoding RNAs, all of which act as epigenetic regulators of vascular wall structure and function. The progress in testing small molecules and oligonucleotide-based drugs in PAH models is summarized.

The role of disturbed blood flow in the development of pulmonary arterial hypertension: lessons from preclinical animal models

2013 ◽  
Vol 305 (1) ◽  
pp. L1-L14 ◽  
Author(s):  
Michael G. Dickinson ◽  
Beatrijs Bartelds ◽  
Marinus A. J. Borgdorff ◽  
Rolf M. F. Berger
Keyword(s):  
Blood Flow ◽  
Pulmonary Arterial Hypertension ◽  
Animal Models ◽  
Arterial Hypertension ◽  
Human Disease ◽  
Vascular Remodeling ◽  
Pulmonary Blood Flow ◽  
Current Knowledge ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasoproliferative disorder characterized by the development of unique neointimal lesions, including concentric laminar intima fibrosis and plexiform lesions. Although the histomorphology of neointimal lesions is well described, the pathogenesis of PAH and neointimal development is largely unknown. After three decades of PAH pathobiology research the focus has shifted from vasoconstriction towards a mechanism of cancer-like angioproliferation. In this concept the role of disturbed blood flow is seen as an important trigger in the development of vascular remodeling. For instance, in PAH associated with congenital heart disease, increased pulmonary blood flow (i.e., systemic-to-pulmonary shunt) is an essential trigger for the occurrence of neointimal lesions and PAH development. Still, questions remain about the exact role of these blood flow characteristics in disease progression. PAH animal models are important for obtaining insight in new pathobiological processes and therapeutical targets. However, as for any preclinical model the pathophysiological mechanism and clinical course has to be comparable to the human disease that it mimics. This means that animal models mimicking human PAH ideally are characterized by: a hit recognized in human disease (e.g., altered pulmonary blood flow), specific vascular remodeling resembling human neointimal lesions, and disease progression that leads to right ventriclular dysfunction and death. A review that underlines the current knowledge of PAH due to disturbed flow is still lacking. In this review we will summarize the current knowledge obtained from PAH animal models associated with disturbed pulmonary blood flow and address questions for future treatment strategies for PAH.

Caspase-4/11–Mediated Pulmonary Artery Endothelial Cell Pyroptosis Contributes to Pulmonary Arterial Hypertension

Hypertension ◽  
2022 ◽  
Author(s):  
Yusi Wu ◽  
Bingjie Pan ◽  
Zhen Zhang ◽  
Xiaohui Li ◽  
Yiping Leng ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Endothelial Cell Function ◽  
Pulmonary Arterial ◽  
Arterial Endothelial Cells

Background: Endothelial dysfunction enhances vascular inflammation, which initiates pulmonary arterial hypertension (PAH) pathogenesis, further induces vascular remodeling and right ventricular failure. Activation of inflammatory caspases is an important initial event at the onset of pyroptosis. Studies have shown that caspase-1–mediated pyroptosis has played a crucial role in the pathogenesis of PAH. However, the role of caspase-11, another inflammatory caspase, remains to be elucidated. Therefore, the purpose of this study was to clarify the role of caspase-11 in the development of PAH and its mechanism on endothelial cell function. Methods: The role of caspase-11 in the progression of PAH and vascular remodeling was assessed in vivo. In vitro, the effect of caspase-4 silencing on the human pulmonary arterial endothelial cells pyroptosis was determined. Results: We confirmed that caspase-11 and its human homolog caspase-4 were activated in PAH animal models and TNF (tumor necrosis factor)-α–induced human pulmonary arterial endothelial cells. Caspase-11 −/− relieved right ventricular systolic pressure, right ventricle hypertrophy, and vascular remodeling in Sugen-5416 combined with chronic hypoxia mice model. Meanwhile, pharmacological inhibition of caspase-11 with wedelolactone exhibited alleviated development of PAH on the monocrotaline-induced rat model. Moreover, knockdown of caspase-4 repressed the onset of TNF-α–induced pyroptosis in human pulmonary arterial endothelial cells and inhibited the activation of pyroptosis effector GSDMD (gasdermin D) and GSDME (gasdermin E). Conclusions: These observations identified the critical role of caspase-4/11 in the pyroptosis pathway to modulate pulmonary vascular dysfunction and accelerate the progression of PAH. Our findings provide a potential diagnostic and therapeutic target in PAH.

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.

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