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.
Rathinasabapathy et al. Caveolin-1 Mutation Mediates PAH Defects Conclusions: The Cav1 mutation identified in human patients in 2012 is molecularly similar to a knockout of Cav1. It results in not only metabolic deficiencies and mild pulmonary hypertension, as expected, but also an inflammatory phenotype and reduced spontaneous exercise.
Poor zinc absorption causes zinc deficiency, leading to skin, gut, and immune pathologies, and psychiatric changes, and are potentially life threatening in infants and children. This can be caused by dietary deficiencies, but also inherited mutations of the ZIP4 gene. Objective Although zinc complexed with organic molecules have previously been shown to have better uptake, we hypothesized that bonding the zinc to the amino group would be less liable to breakdown in the gut than zinc complexed to hydroxy acids, leading to higher bioavailability. Methods We treated wild‐type and mice with inducible universal knockout of one copy of the ZIP4 gene with reduced zinc diet (15 ppm) ad libitum, either in the form of amino acid complexed (CSK18271) or hydroxy acid complex (CSK18273) zinc in an otherwise nutritionally complete diet. Weight was measured at weekly intervals, and mice placed in metabolic phenotyping chambers for a week near the end of the trial. Results We found that ZIP4+/− mice fed CSK18271 had weight gain comparable to wild‐type mice; wild‐type mice fed CSK18273 had lower weight gain, indicating bioavailability was lower even with intact zinc transporter. Zip4+/− mice fed CSK18273 had the worst overall weight gain. Metabolic phenotyping chambers found an increase in respiratory exchange rate (RER) and water intake in the Zip4+/− mice, indicating reduced kidney function in the heterozygous knockout mice, which was compensated for functionally by CSK18271 diet. Conclusions Zinc complexed to the amine group has higher bioavailability than zinc complexed to the hydroxyl group in amino acids, likely because of increased resistance to degradation in the gut. This results in improved weight gain in both wild‐type and Zip4+/− animals. Support or Funding Information The work was funded by Vanderbilt University Medical Center internal funds.
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