The role of ATG-7 contributes to pulmonary hypertension by impacting vascular remodeling

Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodeling. The hypoxia-inducible transcription factors (HIFs) HIF-1α and HIF-2α are known to contribute to the process of hypoxic pulmonary vascular remodeling; however, the specific role of pulmonary endothelial HIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2α is a critical regulator of hypoxia-induced pulmonary arterial hypertension. The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2α deletion. The RVSP of mice lacking HIF-2α in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic WT mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1α exposed to hypoxia. Endothelial HIF-2α deletion also protected mice from hypoxia remodeling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2α, likewise attenuated many of the pathophysiological symptoms associated with hypoxic pulmonary hypertension. We propose a mechanism whereby chronic hypoxia enhances HIF-2α stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia.

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Experimental intravascular hemolysis induces hemodynamic and pathological pulmonary hypertension: association with accelerated purine metabolism

Pulmonary Circulation ◽

10.1177/2045894018791557 ◽

2018 ◽

Vol 8 (3) ◽

pp. 204589401879155 ◽

Cited By ~ 5

Author(s):

Victor P. Bilan ◽

Frank Schneider ◽

Enrico M. Novelli ◽

Eric E. Kelley ◽

Sruti Shiva ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Rat Model ◽

Vascular Remodeling ◽

Purine Nucleoside Phosphorylase ◽

Autologous Blood ◽

Systolic Pressure ◽

Per Se ◽

Parenchymal Injury

Pulmonary hypertension (PH) is emerging as a serious complication associated with hemolytic disorders, and plexiform lesions (PXL) have been reported in patients with sickle cell disease (SCD). We hypothesized that repetitive hemolysis per se induces PH and angioproliferative vasculopathy and evaluated a new mechanism for hemolysis-associated PH (HA-PH) that involves the release of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) from erythrocytes. In healthy rats, repetitive administration of hemolyzed autologous blood (HAB) for 10 days produced reversible pulmonary parenchymal injury and vascular remodeling and PH. Moreover, the combination of a single dose of Sugen-5416 (SU, 200 mg/kg) and 10-day HAB treatment resulted in severe and progressive obliterative PH and formation of PXL (Day 26, right ventricular peak systolic pressure (mmHg): 26.1 ± 1.1, 41.5 ± 0.5 and 85.1 ± 5.9 in untreated, HAB treated and SU+HAB treated rats, respectively). In rats, repetitive administration of HAB increased plasma ADA activity and reduced urinary adenosine levels. Similarly, SCD patients had higher plasma ADA and PNP activity and accelerated adenosine, inosine, and guanosine metabolism than healthy controls. Our study provides evidence that hemolysis per se leads to the development of angioproliferative PH. We also report the development of a rat model of HA-PH that closely mimics pulmonary vasculopathy seen in patients with HA-PH. Finally, this study suggests that in hemolytic diseases released ADA and PNP may increase the risk of PH, likely by abolishing the vasoprotective effects of adenosine, inosine and guanosine. Further characterization of this new rat model of hemolysis-induced angioproliferative PH and additional studies of the role of purines metabolism in HA-PH are warranted.

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55th Bowditch Lecture: Effects of chronic hypoxia on the pulmonary circulation: Role of HIF-1

Journal of Applied Physiology ◽

10.1152/japplphysiol.00843.2012 ◽

2012 ◽

Vol 113 (9) ◽

pp. 1343-1352 ◽

Cited By ~ 17

Author(s):

Larissa A. Shimoda

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Circulation ◽

Vascular Remodeling ◽

Chronic Hypoxia ◽

Critical Role ◽

Hypoxia Inducible Factor ◽

Hypoxia Inducible Factor 1 ◽

Pulmonary Arterial ◽

Expression And Activity

When exposed to chronic hypoxia (CH), the pulmonary circulation responds with enhanced contraction and vascular remodeling, resulting in elevated pulmonary arterial pressures. Our work has identified CH-induced alterations in the expression and activity of several ion channels and transporters in pulmonary vascular smooth muscle that contribute to the development of hypoxic pulmonary hypertension and uncovered a critical role for the transcription factor hypoxia-inducible factor-1 (HIF-1) in mediating these responses. Current work is focused on the regulation of HIF in the chronically hypoxic lung and evaluation of the potential for pharmacological inhibitors of HIF to prevent, reverse, or slow the progression of pulmonary hypertension.

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The Effects of Vasoactive Agents on Impedance Measures in the Pulmonary Circulation of Mice

ASME 2007 Summer Bioengineering Conference ◽

10.1115/sbc2007-176450 ◽

2007 ◽

Author(s):

Rebecca Vanderpool ◽

Naomi C. Chesler

Keyword(s):

Pulmonary Hypertension ◽

Right Ventricular ◽

Vascular Remodeling ◽

Input Resistance ◽

Chronic Obstructive ◽

Wave Reflections ◽

Pulmonary Hemodynamics ◽

Vascular Impedance ◽

Before And After

Pulmonary hypertension is a potentially fatal disease, resulting from chronic obstructive or interstitial lung disease, recurrent pulmonary emboli, antecedent heart disease, hypoxia or other unknown causes [1]. Pulmonary hypertension causes vascular remodeling with smooth muscle cell (SMC) hyperplasia and hypertrophy and accumulation of collagen and elastin [2]. This remodeling increases pulmonary vascular resistance, which can lead to increases in steady right ventricular work [3]. The effects of remodeling on pulmonary vascular impedance, which determines pulsatile right ventricular work, remain incompletely described. We have previously quantified the effects of chronic hypoxia-induced pulmonary hypertension (HPH) on pulmonary vascular impedance [4] but did not investigate the role of SMC tone either before or after HPH. The aim of this study was to investigate the effects of normal and increased SMC tone on pulsatile pulmonary hemodynamics before and after HPH-induced pulmonary vascular remodeling. We hypothesized that SMC contraction would increase input resistance but decrease the speed of wave reflections. We also hypothesized that increased arteriolar muscularization after HPH would lead to greater increases in resistance and greater decreases in wave reflections with increased SMC tone.

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Role of urokinase type plasminogen (uPA) in pulmonary vascular remodeling in a murine model of hypoxia induced pulmonary hypertension

Pneumologie ◽

10.1055/s-2005-925514 ◽

2006 ◽

Vol 59 (12) ◽

Author(s):

BK Dahal ◽

RT Schermuly ◽

P Markat ◽

C Ruppert ◽

R Schmidt ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Murine Model ◽

Vascular Remodeling ◽

Pulmonary Vascular Remodeling

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Abstract 353: Triciribine, a Selective Akt Inhibitor, Inhibits Myofibroblast Differentiation and Ameliorates Pulmonary Vascular Remodeling in Pulmonary Hypertension

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.353 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Payaningal R Somanath ◽

Maha Abdalla

Keyword(s):

Extracellular Matrix ◽

Pulmonary Hypertension ◽

Vascular Remodeling ◽

Therapeutic Option ◽

Matrix Metalloproteases ◽

Confocal Imaging ◽

Extracellular Matrix Protein ◽

Myofibroblast Differentiation ◽

Akt Inhibitor

Objectives: Idiopathic pulmonary fibrosis (IPF) is an incurable, chronic and progressive disease with severely poor prognosis and often leads to pulmonary hypertension (PH). Persistent myofibroblast (MF) differentiation in response to TGFβ, marked by de novo expression of αSMA stress fibers, is the central orchestrator of tissue fibrosis and vasculopathy. Our previous studies indicated the integral role of Akt in myofibroblast differentiation and fibrosis. Here, we investigated the efficacy of Triciribine (TCBN), a selective Akt inhibitor, currently in clinical trials for cancer therapy, as a potential therapeutic option for IPF and PH. Methods: WT and Akt1 null mice, as well as those treated with TCBN were subjected to 3 week hypoxia along with normoxia control, and the lungs were used for imaging and western analysis to study the biochemical, structural and vascular changes in the lungs. Cutting edge techniques such as microfil-cast based vascular imaging, confocal imaging and analysis of extracellular matrix protein turnover was performed for the data collection and analysis. Results: Under hypoxia, WT mice exhibited robust vascular remodeling leading to thickening of the artery wall, reduction in lumen size and loss of capillaries in the lungs. This effect was significantly less in Akt1 null mice. Treatment with TCBN significantly ameliorated vascular remodeling in mice due to hypoxia, and resulted in normalization of the vasculature with increased lumen size, reduced wall thickness and increased number of capillary branches as compared to untreated controls. TCBN also affected expression of a number of different extracellular matrix proteins and matrix metalloproteases in addition to changes in the expression of contractile proteins alpha-actin, myocardin and serum response factor in the adventitial fibroblasts. Conclusions: Our results demonstrate the crucial role of Akt as an integral mediator of MF differentiation in IPF and PH. Further, TCBN could potentially be a therapeutic option for IPF and PH.

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Role of epigenetics in pulmonary hypertension

AJP Cell Physiology ◽

10.1152/ajpcell.00314.2013 ◽

2014 ◽

Vol 306 (12) ◽

pp. C1101-C1105 ◽

Cited By ~ 25

Author(s):

Tara V. Saco ◽

Prasanna Tamarapu Parthasarathy ◽

Young Cho ◽

Richard F. Lockey ◽

Narasaiah Kolliputi

Keyword(s):

Pulmonary Hypertension ◽

Vascular Remodeling ◽

Histone Deacetylase Inhibitors ◽

Dna Methyltransferases ◽

Lesion Formation ◽

Plexiform Lesion ◽

Medial Hypertrophy ◽

Pathologic Processes ◽

Epigenetic Research

A significant amount of research has been conducted to examine the pathologic processes and epigenetic mechanisms contributing to peripheral hypertension. However, few studies have been carried out to understand the vascular remodeling behind pulmonary hypertension (PH), including peripheral artery muscularization, medial hypertrophy and neointima formation in proximal arteries, and plexiform lesion formation. Similarly, research examining some of the epigenetic principles that may contribute to this vascular remodeling, such as DNA methylation and histone modification, is minimal. The understanding of these principles may be the key to developing new and more effective treatments for PH. The purpose of this review is to summarize epigenetic research conducted in the field of hypertension that could possibly be used to understand the epigenetics of PH. Possible future therapies that could be pursued using information from these studies include selective histone deacetylase inhibitors and targeted DNA methyltransferases. Both of these could potentially be used to silence proproliferative or antiapoptotic genes that lead to decreased smooth muscle cell proliferation. Epigenetics may provide a glimmer of hope for the eventual improved treatment of this highly morbid and debilitating disease.

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