Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by arteriopathy in the small to medium-sized distal pulmonary arteries, often accompanied by infiltration of inflammatory cells. Aryl hydrocarbon receptor (AHR), a nuclear receptor/transcription factor, detoxifies xenobiotics and regulates the differentiation and function of various immune cells. However, the role of AHR in the pathogenesis of PAH is largely unknown. Here, we explore the role of AHR in the pathogenesis of PAH. AHR agonistic activity in serum was significantly higher in PAH patients than in healthy volunteers and was associated with poor prognosis of PAH. Sprague–Dawley rats treated with the potent endogenous AHR agonist, 6-formylindolo[3,2-b]carbazole, in combination with hypoxia develop severe pulmonary hypertension (PH) with plexiform-like lesions, whereas Sprague–Dawley rats treated with the potent vascular endothelial growth factor receptor 2 inhibitors did not. Ahr-knockout (Ahr−/−) rats generated using the CRISPR/Cas9 system did not develop PH in the SU5416/hypoxia model. A diet containing Qing-Dai, a Chinese herbal drug, in combination with hypoxia led to development of PH in Ahr+/+ rats, but not in Ahr−/− rats. RNA-seq analysis, chromatin immunoprecipitation (ChIP)-seq analysis, immunohistochemical analysis, and bone marrow transplantation experiments show that activation of several inflammatory signaling pathways was up-regulated in endothelial cells and peripheral blood mononuclear cells, which led to infiltration of CD4+ IL-21+ T cells and MRC1+ macrophages into vascular lesions in an AHR-dependent manner. Taken together, AHR plays crucial roles in the development and progression of PAH, and the AHR-signaling pathway represents a promising therapeutic target for PAH.

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Effect of TSN3015 on the development of pulmonary arterial hypertension in male Sprague-Dawley rats

Journal of Pharmacological and Toxicological Methods ◽

10.1016/j.vascn.2019.05.086 ◽

2019 ◽

Vol 99 ◽

pp. 106595

Author(s):

Peter B. Senese ◽

Kimberly Doherty ◽

David Bullough ◽

Vinicius Carreira ◽

Michael Gralinski

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Pulmonary Arterial

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Rosiglitazone Attenuated Endothelin-1-Induced Vasoconstriction of Pulmonary Arteries in the Rat Model of Pulmonary Arterial Hypertension via Differential Regulation of ET-1 Receptors

PPAR Research ◽

10.1155/2014/374075 ◽

2014 ◽

Vol 2014 ◽

pp. 1-6 ◽

Cited By ~ 12

Author(s):

Yahan Liu ◽

Xiao Yu Tian ◽

Yu Huang ◽

Nanping Wang

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Pulmonary Arteries ◽

Progressive Increase ◽

Differential Regulation ◽

Peroxisome Proliferator ◽

Sprague Dawley ◽

Peroxisome Proliferator Activated Receptor ◽

Sprague Dawley Rats ◽

Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary arterial pressure leading to right ventricular failure and death. Activation of the endothelin (ET)-1 system has been demonstrated in plasma and lung tissue of PAH patients as well as in animal models of PAH. Recently, peroxisome proliferator-activated receptorγ(PPARγ) agonists have been shown to ameliorate PAH. The present study aimed to investigate the mechanism for the antivasoconstrictive effects of rosiglitazone in response to ET-1 in PAH. Sprague-Dawley rats were exposed to chronic hypoxia (10% oxygen) for 3 weeks. Pulmonary arteries from PAH rats showed an enhanced vasoconstriction in response to ET-1. Treatment with PPARγagonist rosiglitazone (20 mg/kg per day) with oral gavage for 3 days attenuated the vasocontractive effect of ET-1. The effect of rosiglitazone was lost in the presence ofL-NAME, indicating a nitric oxide-dependent mechanism. Western blotting revealed that rosiglitazone increasedETBRbut decreasedETARlevel in pulmonary arteries from PAH rats.ETBRantagonist A192621 diminished the effect of rosiglitazone on ET-1-induced contraction. These results demonstrated that rosiglitazone attenuated ET-1-induced pulmonary vasoconstriction in PAH through differential regulation of the subtypes of ET-1 receptors and, thus, provided a new mechanism for the therapeutic use of PPARγagonists in PAH.

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HIGH MORTALITY OF FISCHER VS. SPRAGUE-DAWLEY RATS IN THE SU5416 MODEL OF SEVERE PULMONARY ARTERIAL HYPERTENSION IS ASSOCIATED WITH STRAIN-SPECIFIC FAILURE OF RIGHT VENTRICULAR ADAPTATION: EFFECTS OF CARDIAC-SPECIFIC THERAPY WITH CARDIOTROPHIN-1

Canadian Journal of Cardiology ◽

10.1016/j.cjca.2015.07.310 ◽

2015 ◽

Vol 31 (10) ◽

pp. S142-S143

Author(s):

C. Suen ◽

M. Al-Ghani ◽

B. Jiang ◽

Y. Deng ◽

M. Taha ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Right Ventricular ◽

High Mortality ◽

Sprague Dawley ◽

Specific Therapy ◽

Sprague Dawley Rats ◽

Pulmonary Arterial ◽

Severe Pulmonary Arterial Hypertension ◽

Adaptation Effects

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Rosuvastatin ameliorates the development of pulmonary arterial hypertension in the transgenic (mRen2)27 rat

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00048.2009 ◽

2009 ◽

Vol 297 (3) ◽

pp. H1128-H1139 ◽

Cited By ~ 21

Author(s):

Vincent G. DeMarco ◽

Javad Habibi ◽

Adam T. Whaley-Connell ◽

Rebecca I. Schneider ◽

James R. Sowers ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Proliferation ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Systolic Pressure ◽

Left Ventricular ◽

No Synthase ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Pulmonary Arterial

We have recently reported that transgenic (mRen2)27 rats (Ren2 rats) exhibit pulmonary arterial hypertension (PAH), which is, in part, mediated by oxidative stress. Since 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) exhibit beneficial vascular effects independent of cholesterol synthesis, we hypothesized that rosuvastatin (RSV) treatment ameliorates PAH and pulmonary vascular remodeling in Ren2 rats, in part, by reducing oxidative stress. Six-week-old male Ren2 and Sprague-Dawley rats received RSV (10 mg·kg−1·day−1 ip) or vehicle for 3 wk. After treatment, right ventricular systolic pressure (RVSP) and mean arterial pressure (MAP) were measured. To evaluate treatment effects on pulmonary arteriole remodeling, morphometric analyses were performed to quantitate medial thickening and cell proliferation, whereas whole lung samples were used to quantitate the levels of 3-nitrotyrosine, superoxide, stable nitric oxide (NO) metabolites [nitrates and nitrites (NO x)], and expression of NO synthase isoforms. In the Ren2 rat, RVSP is normal at 5 wk of age, PAH develops between 5 and 7 wk of age, and the elevated pressure is maintained with little variation through 13 wk. At 8 wk of age, left ventricular function and blood gases were normal in the Ren2 rat. Ren2 rats exhibited elevations in medial hypertrophy due to smooth muscle cell proliferation, 3-nitrotyrosine, NO x, NADPH oxidase activity, and endothelial NO synthase expression compared with Sprague-Dawley rats. RSV significantly blunted the increase in RVSP but did not reduce MAP in the Ren2 rat; additionally, RSV significantly attenuated the elevated parameters examined in the Ren2 rat. These data suggest that statins may be a clinically viable adjunct treatment of PAH through reducing peroxynitrite formation.

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GENETIC BASIS FOR SEX-RELATED HYPER-RESPONSIVENESS TO SEVERE PULMONARY ARTERIAL HYPERTENSION INDUCED BY SU5416 IN A SUB-STRAIN OF SPRAGUE DAWLEY RATS

Canadian Journal of Cardiology ◽

10.1016/j.cjca.2015.07.179 ◽

2015 ◽

Vol 31 (10) ◽

pp. S79-S80

Author(s):

K.R. Chaudhary ◽

Y. Deng ◽

A. Yang ◽

D.J. Stewart

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Genetic Basis ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Pulmonary Arterial ◽

Severe Pulmonary Arterial Hypertension

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NOVEL WIDESPREAD MUTATION IN HIF1α IN SPRAGUE DAWLEY RATS IS ASSOCIATED WITH HYPER-RESPONSIVENESS TO SU5416 AND SEVERE PULMONARY ARTERIAL HYPERTENSION ONLY IN CONJUNCTION WITH OTHER SUB-STRAIN-SPECIFIC GENETIC MODIFIERS

Canadian Journal of Cardiology ◽

10.1016/j.cjca.2016.07.246 ◽

2016 ◽

Vol 32 (10) ◽

pp. S159

Author(s):

K.R. Chaudhary ◽

Y. Deng ◽

A. Yang ◽

E. Cuppen ◽

D.J. Stewart

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Genetic Modifiers ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Pulmonary Arterial ◽

Severe Pulmonary Arterial Hypertension

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

Advances in Pulmonary Hypertension ◽

10.21693/1933-088x.15.1.12 ◽

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.

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