Altered Gene Expression in Pulmonary Tissue of Tryptophan Hydroxylase-1 Knockout Mice: Implications for Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary vascular resistance with subsequent remodeling and right ventricular hypertrophy. Vascular reactivity and ventricular function were investigated in rats with monocrotaline-induced PAH and treated with a new N-acylhydrazone derivative named as LASSBio-1359. METHODS: Protocols were approved by Animal Care and Use Committee at Universidade Federal do Rio de Janeiro. Male Wistar rats received a single i.p. injection of monocrotaline (MCT) (60 mg/kg) for PAH induction and were randomly divided in groups which were treated with: saline, vehicle and LASSBio-1359 (50 mg/kg p.o.). After 14 days of treatment, some parameters were evaluated: pulmonary acceleration time (PAT); right ventricular systolic pressure (RVSP); vascular reactivity to acetylcholine; expression of iNOS in pulmonary tissue; wall thickness of pulmonary artery (PAWT). Results: PAT (ms) was increased from 26.2 ± 2.8 to 41.3 ± 3.9 in PAH group treated with vehicle (n=8, p<0.05) and was reduced to 24.2 ± 1.7 when PAH group was treated with LASSBio-1359. RVSP (mmHg) increased from 26.0 ± 2.0 to 55.2 ± 2.3 in PAH group (p<0.05) but was similar to control after treatment with LASSBio-1359 (31.8 ± 2.3 mm Hg). Ratio of right ventricle and body weight (mg/g) was 0.66 ± 0.02, 1.63 ± 0.16 and 0.87 ± 0.10 for control, vehicle- and LASSBio-1359-treated PAH groups, respectively. PAH promoted ventricular dysfunction which was reduced by LASSBio-1359. The pulmonary artery maximum relaxation (%) was 57.3 ± 5.5, 43.6 ± 1.2 and 61.4 ± 8.4 for control, vehicle and LASSBio-1359-treated groups indicating that PAH promoted endothelium injury which was recovered by LASSBio-1359. iNOS expression in pulmonary tissue was increased from 0.48 ± 1.31 to 0.98 ± 3.14 in PAH group and reduced to 0.53 ± 1.83 in rats treated with LASSBio-1359. The PAWT (%) were increased from 74.1 ± 1.3 to 90.2 ± 2.7 in PAH group (p<0.05) but was 74.4 ± 1.3 when treated with LASSBio-1359. This compound showed an in vitro vasodilatory activity mediated by activation of adenosinergic A2A receptor. Conclusion: LASSBio-1359 reduced ventricular and vascular dysfunction in monocrotaline-induced PAH in rats indicating a possible new alternative to treat PAH.

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Patients with systemic sclerosis-associated pulmonary arterial hypertension express a genomic signature distinct from patients with interstitial lung disease

Journal of Scleroderma and Related Disorders ◽

10.1177/2397198318764780 ◽

2018 ◽

Vol 3 (3) ◽

pp. 242-248 ◽

Cited By ~ 6

Author(s):

Matthew Moll ◽

Romy B Christmann ◽

Yuqing Zhang ◽

Michael L Whitfield ◽

Yu Mei Wang ◽

...

Keyword(s):

Gene Expression ◽

Systemic Sclerosis ◽

Pulmonary Arterial Hypertension ◽

Interstitial Lung Disease ◽

Arterial Hypertension ◽

Lung Disease ◽

Expression Profiles ◽

Area Under The Curve ◽

Gene Expression Profiles ◽

Pulmonary Arterial

Objective: Pulmonary arterial hypertension and interstitial lung disease are major causes of mortality in systemic sclerosis. We used a previously identified microarray biomarker to determine whether systemic sclerosis-pulmonary arterial hypertension and systemic sclerosis-interstitial lung disease patients demonstrate distinct gene expression profiles. Methods: Peripheral blood mononuclear cells were collected from healthy controls ( n = 10), systemic sclerosis patients without pulmonary hypertension (systemic sclerosis-no pulmonary arterial hypertension, n = 39), and systemic sclerosis-pulmonary arterial hypertension patients ( n = 21; mean pulmonary arterial pressure ≥25, pulmonary capillary wedge pressure ≤15, and pulmonary vascular resistance ≥3 Wood units) diagnosed by right heart catheterization. Systemic sclerosis-interstitial lung disease patients were defined as those with evidence of fibrosis on chest computed tomography and significant restriction (forced vital capacity <70% predicted, n = 11). Systemic sclerosis-pulmonary arterial hypertension biomarker included 69 genes selected by unbiased statistical screening of three publicly available microarray studies. RNA levels were measured by NanoString Technologies. Gene expression levels that were significantly correlated with pulmonary arterial hypertension (multiple statistical measures) were chosen as inputs into a forward selection logistic regression model. Results: When interstitial lung disease patients were included ( n = 64), four genes (S100P, CD8B1, CCL2, and TIMP1) and male sex predicted pulmonary arterial hypertension with a high level of accuracy (area under the curve = 0.83). Without interstitial lung disease patients ( n = 53), two genes (THBS1 and CD8B1) and male sex predicted pulmonary arterial hypertension with a high level of accuracy (area under the curve = 0.80). When examining systemic sclerosis patients with borderline elevated pulmonary pressures (mean pulmonary arterial pressure = 21–24 mmHg), gene expression changes closely resembled the systemic sclerosis-pulmonary arterial hypertension group, except for THBS1. Conclusion: Systemic sclerosis-pulmonary arterial hypertension and systemic sclerosis-interstitial lung disease have similar but distinct gene expression profiles. Many gene expression changes occur early in the disease course, potentially allowing early detection. THBS1 appears to be an important mediator in the development of pulmonary arterial hypertension-predominant phenotype. Further prospective investigation is warranted.

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Altered gene expression in striatal projection neurons in CB1 cannabinoid receptor knockout mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.96.10.5786 ◽

1999 ◽

Vol 96 (10) ◽

pp. 5786-5790 ◽

Cited By ~ 86

Author(s):

H. Steiner ◽

T. I. Bonner ◽

A. M. Zimmer ◽

S. T. Kitai ◽

A. Zimmer

Keyword(s):

Gene Expression ◽

Knockout Mice ◽

Cannabinoid Receptor ◽

Projection Neurons ◽

Altered Gene Expression ◽

Cb1 Cannabinoid Receptor ◽

Striatal Projection Neurons ◽

Altered Gene

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Gene Expression Profiling In Peripheral Blood Mononuclear Cells Of Patients With Idiopathic And Heritable Pulmonary Arterial Hypertension

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a1885 ◽

2012 ◽

Author(s):

Silvia Cantoni ◽

Riccardo Tassinari ◽

Margherita Galletti ◽

Alessandro Guffanti ◽

Elena Brini ◽

...

Keyword(s):

Gene Expression ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Peripheral Blood Mononuclear Cells ◽

Expression Profiling ◽

Mononuclear Cells ◽

Peripheral Blood Mononuclear ◽

Blood Mononuclear Cells ◽

Pulmonary Arterial ◽

Heritable Pulmonary Arterial Hypertension

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ADMINISTRATION OF IL-6 AFTER CLP RESTORES ALTERED GENE EXPRESSION BUT ELIMINATES MORTALITY IN IL-6 KNOCKOUT MICE.

Shock ◽

10.1097/00024382-200306001-00214 ◽

2003 ◽

Vol 19 (Supplement) ◽

pp. 73

Author(s):

N. R. Raj ◽

P. Adler ◽

P. K. Kim ◽

C. S. Deutschman

Keyword(s):

Gene Expression ◽

Knockout Mice ◽

Altered Gene Expression ◽

Altered Gene

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Gene expression profile in flow-associated pulmonary arterial hypertension with neointimal lesions

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00106.2009 ◽

2010 ◽

Vol 298 (4) ◽

pp. L483-L491 ◽

Cited By ~ 28

Author(s):

Mirjam E. van Albada ◽

Beatrijs Bartelds ◽

Hans Wijnberg ◽

Saffloer Mohaupt ◽

Michael G. Dickinson ◽

...

Keyword(s):

Gene Expression ◽

Blood Flow ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Pulmonary Blood Flow ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Response To Therapy ◽

High Morbidity ◽

Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a pulmonary angioproliferative disease with high morbidity and mortality, characterized by a typical pattern of pulmonary vascular remodeling including neointimal lesions. In congenital heart disease, increased pulmonary blood flow has appeared to be a key mediator in the development of these characteristic lesions, but the molecular mechanisms underlying the pulmonary vascular lesions are largely unknown. We employed a rat model of flow-associated PAH, which induced specific pulmonary neointimal lesions. We identified gene expression profiles in rats specifically related to the addition of increased pulmonary blood flow to monocrotaline and the associated occurrence of neointimal lesions. Increased pulmonary blood flow induced the expression of the transcription factors activating transcription factor-3 (ATF3) and early growth response factor-1 (EGR-1), for which presence was confirmed in neointimal lesions. Monocrotaline alone induced increased numbers of activated mast cells and their products. We further identified molecular pathways that may be involved in treatment with the prostacyclin analog iloprost, a vasoactive compound with clinically beneficial effects in patients with PAH, which were similar to pathways described in samples from patient studies. These pathways, associated with the development of angioproliferative lesions as well as with the response to therapy in PAH, may provide new therapeutic targets.

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ALDH1A3 Coordinates Metabolism with Gene Regulation in Pulmonary Arterial Hypertension

Circulation ◽

10.1161/circulationaha.120.048845 ◽

2021 ◽

Author(s):

Dan Li ◽

Ning-Yi Shao ◽

Jan-Renier Moonen ◽

Zhixin Zhao ◽

Minyi Shi ◽

...

Keyword(s):

Gene Expression ◽

Pulmonary Hypertension ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Cell Function ◽

Chromatin Modification ◽

Major Pathway ◽

Energy Needs ◽

Dividing Cells ◽

Pulmonary Arterial

Background: Metabolic alterations provide substrates that influence chromatin structure to regulate gene expression that determines cell function in health and disease. Heightened proliferation of smooth muscle cells (SMC) leading to the formation of a neointima is a feature of pulmonary arterial hypertension (PAH) and systemic vascular disease. Increased glycolysis is linked to the proliferative phenotype of these SMC. Methods: RNA Sequencing was applied to pulmonary arterial (PA) SMC from PAH patients with and without a BMPR2 mutation vs. control PASMC to uncover genes required for their heightened proliferation and glycolytic metabolism. Assessment of differentially expressed genes established metabolism as a major pathway, and the most highly upregulated metabolic gene in PAH PASMC was aldehyde dehydrogenase family 1 member 3 ( ALDH1A3 ), an enzyme previously linked to glycolysis and proliferation in cancer cells and systemic vascular SMC. We determined if these functions are ALDH1A3-dependent in PAH PASMC, and if ALDH1A3 is required for the development of pulmonary hypertension in a transgenic mouse. Nuclear localization of ALDH1A3 in PAH PASMC led us to determine whether and how this enzyme coordinately regulates gene expression and metabolism in PAH PASMC. Results: ALDH1A3 mRNA and protein were increased in PAH vs control PASMC, and ALDH1A3 was required for their highly proliferative and glycolytic properties. Mice with Aldh1a3 deleted in SMC did not develop hypoxia-induced PA muscularization or pulmonary hypertension. Nuclear ALDH1A3 converted acetaldehyde to acetate to produce acetyl-CoA to acetylate H3K27, marking active enhancers. This allowed for chromatin modification at nuclear factor Y (NFY)A binding sites via the acetyltransferase KAT2B and permitted NFY mediated transcription of cell cycle and metabolic genes that is required for ALDH1A3-dependent proliferation and glycolysis. Loss of BMPR2 in PAH SMC with or without a mutation upregulated ALDH1A3, and transcription of NFYA and ALDH1A3 in PAH PASMC was β-catenin dependent. Conclusions: Our studies have uncovered a metabolic-transcriptional axis explaining how dividing cells use ALDH1A3 to coordinate their energy needs with the epigenetic and transcriptional regulation of genes required for SMC proliferation. They suggest that selectively disrupting the pivotal role of ALDH1A3 in PAH SMC, but not EC, is an important therapeutic consideration.

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