Kcnk3 mutation causes altered immune function in pulmonary arterial hypertension patients and mouse models

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

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish
Article number5014
JournalInternational journal of molecular sciences
Issue number9
StatePublished - May 1 2021


  • Inflammation
  • KCNK3
  • Lymphocytes
  • Monocytes
  • Pulmonary arterial hypertension


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