scholarly journals Treatment with low-dose tacrolimus inhibits bleeding complications in a patient with hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension

2018 ◽  
Vol 9 (2) ◽  
pp. 204589401880540 ◽  
Author(s):  
N Sommer ◽  
F Droege ◽  
KE Gamen ◽  
U Geisthoff ◽  
H Gall ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Low Dose ◽  
Bleeding Complications ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Beneficial Effects ◽  
Pulmonary Arterial ◽  
End Stage

Pulmonary arterial hypertension (PAH) can be found in patients suffering from a loss-of-function mutation of the gene encoding for the activin receptor-like kinase 1 (ALK-1), a bone morphogenetic protein (BMP) type 1 receptor. Interestingly, ALK-1 mutations also lead to hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disease characterized by arteriovenous malformations (AVMs) leading to potentially life-threatening bleeding complications such as epistaxis. Current therapeutic options for both diseases are limited and often only temporary or accompanied by severe side effects. Here, we report of a patient with a mutation of the ALK-1 gene suffering from both HHT and PAH. Recently, it was shown that tacrolimus increased ALK-1 signaling and had beneficial effects in selected end-stage PAH patients. We thus hypothesized that treatment with tacrolimus may prevent disease progression in this patient. Surprisingly, treatment with low-dose tacrolimus dramatically improved his HHT-associated epistaxis but did not attenuate progression of PAH.

scholarly journals Low-Dose FK506 (Tacrolimus) in End-Stage Pulmonary Arterial Hypertension

2015 ◽  
Vol 192 (2) ◽  
pp. 254-257 ◽  
Author(s):  
Edda Spiekerkoetter ◽  
Yon K. Sung ◽  
Deepti Sudheendra ◽  
Matthew Bill ◽  
Micheala A. Aldred ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Low Dose ◽  
Pulmonary Arterial ◽  
End Stage

scholarly journals KCNK3 Mutation Causes Altered Immune Function in Pulmonary Arterial Hypertension Patients and Mouse Models

2021 ◽  
Vol 22 (9) ◽  
pp. 5014
Author(s):  
James D. West ◽  
Eric D. Austin ◽  
Elise M. Rizzi ◽  
Ling Yan ◽  
Harikrishna Tanjore ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Tone ◽  
Low Dose ◽  
Mononuclear Cells ◽  
Bone Marrow Cells ◽  
Loss Of Function ◽  
Peripheral Blood Mononuclear ◽  
Tissue Samples ◽  
Pulmonary Arterial

Loss of function KCNK3 mutation is one of the gene variants driving hereditary pulmonary arterial hypertension (PAH). KCNK3 is expressed in several cell and tissue types on both membrane and endoplasmic reticulum and potentially plays a role in multiple pathological process associated with PAH. However, the role of various stressors driving the susceptibility of KCNK3 mutation to PAH is unknown. Hence, we exposed kcnk3fl/fl animals to hypoxia, metabolic diet and low dose lipopolysaccharide (LPS) and performed molecular characterization of their tissue. We also used tissue samples from KCNK3 patients (skin fibroblast derived inducible pluripotent stem cells, blood, lungs, peripheral blood mononuclear cells) and performed microarray, immunohistochemistry (IHC) and mass cytometry time of flight (CyTOF) experiments. Although a hypoxic insult did not alter vascular tone in kcnk3fl/fl mice, RNASeq study of these lungs implied that inflammatory and metabolic factors were altered, and the follow-up diet study demonstrated a dysregulation of bone marrow cells in kcnk3fl/fl mice. Finally, a low dose LPS study clearly showed that inflammation could be a possible second hit driving PAH in kcnk3fl/fl mice. Multiplex, IHC and CyTOF immunophenotyping studies on human samples confirmed the mouse data and strongly indicated that cell mediated, and innate immune responses may drive PAH susceptibility in these patients. In conclusion, loss of function KCNK3 mutation alters various physiological processes from vascular tone to metabolic diet through inflammation. Our data suggests that altered circulating immune cells may drive PAH susceptibility in patients with KCNK3 mutation.

scholarly journals Effect of Transcriptional Regulator ID3 on Pulmonary Arterial Hypertension and Hereditary Hemorrhagic Telangiectasia

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Vincent Avecilla
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Transcriptional Regulator ◽  
Inherited Disease ◽  
Loss Of Function ◽  
Morphogenetic Protein ◽  
Pulmonary Arterial ◽  
Inhibitor Of Dna Binding

Pulmonary arterial hypertension (PAH) can be discovered in patients who have a loss of function mutation of activin A receptor-like type 1 (ACVRL1) gene, a bone morphogenetic protein (BMP) type 1 receptor. Additionally, ACVRL1 mutations can lead to hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, an autosomal dominant inherited disease that results in mucocutaneous telangiectasia and arteriovenous malformations (AVMs). Transcriptional regulator Inhibitor of DNA-Binding/Differentiation-3 (ID3) has been demonstrated to be involved in both PAH and HTT; however, the role of its overlapping molecular mechanistic effects has yet to be seen. This review will focus on the existing understanding of how ID3 may contribute to molecular involvement and perturbations thus altering both PAH and HHT outcomes. Improved understanding of how ID3 mediates these pathways will likely provide knowledge in the inhibition and regulation of these diseases through targeted therapies.

miR-223 reverses experimental pulmonary arterial hypertension

2015 ◽  
Vol 309 (6) ◽  
pp. C363-C372 ◽  
Author(s):  
Jolyane Meloche ◽  
Marie Le Guen ◽  
François Potus ◽  
Jérôme Vinck ◽  
Benoit Ranchoux ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Hypoxia Inducible Factor ◽  
Pulmonary Arteries ◽  
Vascular Wall ◽  
Loss Of Function ◽  
Beneficial Effects ◽  
Pulmonary Arterial ◽  
Ventricle Hypertrophy ◽  
Parp 1

Pulmonary arterial hypertension (PAH) is a devastating disease affecting lung vasculature. The pulmonary arteries become occluded due to increased proliferation and suppressed apoptosis of the pulmonary artery smooth muscle cells (PASMCs) within the vascular wall. It was recently shown that DNA damage could trigger this phenotype by upregulating poly(ADP-ribose)polymerase 1 (PARP-1) expression, although the exact mechanism remains unclear. In silico analyses and studies in cancer demonstrated that microRNA miR-223 targets PARP-1. We thus hypothesized that miR-223 downregulation triggers PARP-1 overexpression, as well as the proliferation/apoptosis imbalance observed in PAH. We provide evidence that miR-223 is downregulated in human PAH lungs, distal PAs, and isolated PASMCs. Furthermore, using a gain and loss of function approach, we showed that increased hypoxia-inducible factor 1α, which is observed in PAH, triggers this decrease in miR-223 expression and subsequent overexpression of PARP-1 allowing PAH-PASMC proliferation and resistance to apoptosis. Finally, we demonstrated that restoring the expression of miR-223 in lungs of rats with monocrotaline-induced PAH reversed established PAH and provided beneficial effects on vascular remodeling, pulmonary resistance, right ventricle hypertrophy, and survival. We provide evidence that miR-223 downregulation in PAH plays an important role in numerous pathways implicated in the disease and restoring its expression is able to reverse PAH.

Pulmonary arterial hypertension in families with hereditary hemorrhagic telangiectasia: a 13-year follow-up study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y.-P Zhou ◽  
X Jiang ◽  
Y.-X Zhang ◽  
K Sun ◽  
T.-Y Lian ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Clinical Status ◽  
Development Program ◽  
Resistance Index ◽  
Walking Distance ◽  
Funding Source ◽  
Free Survival ◽  
Pulmonary Arterial

Abstract Background Pulmonary arterial hypertension (PAH) can occur in families with hereditary hemorrhagic telangiectasia (HHT), but it has not been well-characterized. Purpose This study sought to characterize the genetic defects, clinical and hemodynamic features, and outcomes of PAH patients in HHT families. Methods All HHT families with at least one case of PAH investigated in our center from January 2006 to December 2018 were enrolled in the study. We did whole-exome sequencing (WES) or whole-genome sequencing (WGS) to every proband and available family members. The clinical data, hemodynamic features and outcomes of PAH patients were reviewed. Results A total of 64 PAH patients in 57 families were enrolled. Only 7 (12.3%) families had more than one case of PAH. Activin-receptor-like kinase 1 (ALK-1) mutation and Endoglin (ENG) mutation were confirmed in 49 (86.0%) and 3 (5.3%) families and other 5 (8.8%) had no known mutation associated with HHT or PAH. The median age when PAH diagnosis was 22 [9–33] years and female was dominant (70.3%). Most patients (84.4%) had signs of HHT and anemia was recorded in 14 (21.9%) patients. Remarkably, these patients showed severely compromised hemodynamics with elevated mean pulmonary artery pressure (62 [51, 77] mm Hg) and pulmonary vascular resistance index (17.0 [11.2, 22.8] Wood units*m2). Also, impaired exercise capacity was recorded at diagnosis with decreased six-minute walking distance (410 [342–485] meters) and over half (54.7%) were in WHO functional class III or IV. The 1-, 3-, 5- and 10-year transplantation-free survival for the overall PAH patients was 95.0%, 75.9%, 67.1% and 36.4%, respectively. Anemia (HR: 4.24 [1.32–13.65], p=0.016) and CI <2.5 l/min/m2 (HR: 4.39 [1.20–16.09], p=0.026) were independent risk factors for mortality. Conclusions PAH in HHT families is a devastating condition characterized by a young age at PAH diagnosis, poor clinical status and outcomes mainly underlying ALK-1 mutation, which emphasizes the importance to pay attention to this group of patients. Transplantation-free survival Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): The Beijing Natural Science Foundation (7181009), the National Key Research and Development Program of China (2016YFC0901502)

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