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 A Nationwide multicenter registry and biobank program for deep phenotyping of idiopathic and hereditary pulmonary arterial hypertension in Korea: the PAH platform for deep phenotyping in Korean subjects (PHOENIKS) cohort

2019 ◽  
Vol 25 (1) ◽  
Author(s):  
Albert Youngwoo Jang ◽  
◽  
Sungseek Kim ◽  
Su Jung Park ◽  
Hanul Choi ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Personalized Medicine ◽  
Arterial Hypertension ◽  
Clinical Data ◽  
Mononuclear Cells ◽  
Buffy Coat ◽  
Heart Catheterization ◽  
Peripheral Blood Mononuclear ◽  
Pulmonary Arterial ◽  
Deep Phenotyping

Abstract Background Pulmonary arterial hypertension (PAH) is a progressive, chronic disease without curative treatment. Large registry data of these patient populations have been published, although, phenotypic variants within each subtype of PAH have not been elucidated. As interest towards personalized medicine grows, the need for a PAH cohort with a comprehensive understanding of patient phenotypes through multiomics approaches, called deep phenotyping, is on the rise. The PAH Platform for Deep Phenotyping in Korean Subjects (PHOENIKS) cohort is designed to collect clinical data as well as biological specimens for deep phenotyping in patients with idiopathic PAH (IPAH) and heritable PAH (HPAH) in Korea. Methods A total of 17 regional hospitals are currently working on enrolling up to 100 consecutive IPAH/HPAH patients for obtaining clinical data and biological specimens across Korea. The diagnosis of PAH is based on right heart catheterization. All clinical data is stored in a government-based online database. Each participating hospitals collect a whole blood sample from each patient, through which DNA, RNA, serum, plasma, and peripheral blood mononuclear cells will be extracted from the buffy coat layer for further multiomics analysis. Results Not applicable. Conclusions The PHOENIKS cohort is enrolling IPAH and HPAH patients across Korea to determine the prognosis and drug response in different phenotypic variant. The data generated by this cohort are expected to open new doors for personalized medicine in PAH patients of South Korea. Trial registration ClinicalTrials.gov NCT03933579. Registered on May 1st, 2019.

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.

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