KCNK3 Mutation Causes Altered Immune Function in Pulmonary Arterial Hypertension Patients and Mouse Models
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. Howe...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/9/5014 |
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| author | James D. West Eric D. Austin Elise M. Rizzi Ling Yan Harikrishna Tanjore Amber L. Crabtree Christy S. Moore Gladson Muthian Erica J. Carrier David A. Jacobson Rizwan Hamid Peggy L. Kendall Susan Majka Anandharajan Rathinasabapathy |
| author_facet | James D. West Eric D. Austin Elise M. Rizzi Ling Yan Harikrishna Tanjore Amber L. Crabtree Christy S. Moore Gladson Muthian Erica J. Carrier David A. Jacobson Rizwan Hamid Peggy L. Kendall Susan Majka Anandharajan Rathinasabapathy |
| author_sort | James D. West |
| collection | DOAJ |
| description | 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 <i>kcnk3<sup>fl/fl</sup></i> 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 <i>kcnk3<sup>fl/fl</sup></i> 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 <i>kcnk3<sup>fl/fl</sup></i> mice. Finally, a low dose LPS study clearly showed that inflammation could be a possible second hit driving PAH in <i>kcnk3<sup>fl/fl</sup></i> 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. |
| first_indexed | 2024-03-10T11:35:40Z |
| format | Article |
| id | doaj.art-72de54ae655f451f83594e429146876f |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T11:35:40Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-72de54ae655f451f83594e429146876f2023-11-21T18:52:37ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-01229501410.3390/ijms22095014KCNK3 Mutation Causes Altered Immune Function in Pulmonary Arterial Hypertension Patients and Mouse ModelsJames D. West0Eric D. Austin1Elise M. Rizzi2Ling Yan3Harikrishna Tanjore4Amber L. Crabtree5Christy S. Moore6Gladson Muthian7Erica J. Carrier8David A. Jacobson9Rizwan Hamid10Peggy L. Kendall11Susan Majka12Anandharajan Rathinasabapathy13Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USADivision of Allergy and Immunology, Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USADepartment of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USADivision of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USADivision of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USADivision of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Cancer Biology, Biochemistry and Neuropharmacology, School of Medicine, Meharry Medical College, Nashville, TN 37208, USADivision of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USADepartment of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USADivision of Allergy and Immunology, Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USADivision of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, CO 80206, USADivision of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USALoss 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 <i>kcnk3<sup>fl/fl</sup></i> 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 <i>kcnk3<sup>fl/fl</sup></i> 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 <i>kcnk3<sup>fl/fl</sup></i> mice. Finally, a low dose LPS study clearly showed that inflammation could be a possible second hit driving PAH in <i>kcnk3<sup>fl/fl</sup></i> 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.https://www.mdpi.com/1422-0067/22/9/5014pulmonary arterial hypertensioninflammationKCNK3monocyteslymphocytes |
| spellingShingle | James D. West Eric D. Austin Elise M. Rizzi Ling Yan Harikrishna Tanjore Amber L. Crabtree Christy S. Moore Gladson Muthian Erica J. Carrier David A. Jacobson Rizwan Hamid Peggy L. Kendall Susan Majka Anandharajan Rathinasabapathy KCNK3 Mutation Causes Altered Immune Function in Pulmonary Arterial Hypertension Patients and Mouse Models International Journal of Molecular Sciences pulmonary arterial hypertension inflammation KCNK3 monocytes lymphocytes |
| title | KCNK3 Mutation Causes Altered Immune Function in Pulmonary Arterial Hypertension Patients and Mouse Models |
| title_full | KCNK3 Mutation Causes Altered Immune Function in Pulmonary Arterial Hypertension Patients and Mouse Models |
| title_fullStr | KCNK3 Mutation Causes Altered Immune Function in Pulmonary Arterial Hypertension Patients and Mouse Models |
| title_full_unstemmed | KCNK3 Mutation Causes Altered Immune Function in Pulmonary Arterial Hypertension Patients and Mouse Models |
| title_short | KCNK3 Mutation Causes Altered Immune Function in Pulmonary Arterial Hypertension Patients and Mouse Models |
| title_sort | kcnk3 mutation causes altered immune function in pulmonary arterial hypertension patients and mouse models |
| topic | pulmonary arterial hypertension inflammation KCNK3 monocytes lymphocytes |
| url | https://www.mdpi.com/1422-0067/22/9/5014 |
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