FN3K expression in COPD: a potential comorbidity factor for cardiovascular disease
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AuthorsAlderawi, Amr Saleh
Baker, Emma H.
Hitchings, Andrew William
Ortega, Victor E.
Curtis, Jeffrey L.
Dunmore, Simon J.
MetadataShow full item record
AbstractIntroduction Cigarette smoking and oxidative stress are common risk factors for the multi-morbidities associated with chronic obstructive pulmonary disease (COPD). Elevated levels of advanced glycation endproducts (AGE) increase the risk of cardiovascular disease (CVD) comorbidity and mortality. The enzyme fructosamine-3-kinase (FN3K) reduces this risk by lowering AGE levels. Methods The distribution and expression of FN3K protein in lung tissues from stable COPD and control subjects, as well as an animal model of COPD, was assessed by immunohistochemistry. Serum FN3K protein and AGE levels were assessed by ELISA in patients with COPD exacerbations receiving metformin. Genetic variants within the FN3K and FN3K-RP genes were evaluated for associations with cardiorespiratory function in the Subpopulations and Intermediate Outcome Measures in COPD Study cohort. Results This pilot study demonstrates that FN3K expression in the blood and human lung epithelium is distributed at either high or low levels irrespective of disease status. The percentage of lung epithelial cells expressing FN3K was higher in control smokers with normal lung function, but this induction was not observed in COPD patients nor in a smoking model of COPD. The top five nominal FN3K polymorphisms with possible association to decreased cardiorespiratory function (p<0.008–0.02), all failed to reach the threshold (p<0.0028) to be considered highly significant following multi-comparison analysis. Metformin enhanced systemic levels of FN3K in COPD subjects independent of their high-expression or low-expression status. Discussion The data highlight that low and high FN3K expressors exist within our study cohort and metformin induces FN3K levels, highlighting a potential mechanism to reduce the risk of CVD comorbidity and mortality.
CitationAlderawi A, Caramori G, Baker EH, et al. (2020) FN3K expression in COPD: a potential comorbidity factor for cardiovascular disease. BMJ Open Respiratory Research, 7, 000714. doi:10.1136/ bmjresp-2020-000714
JournalBMJ Open Respiratory Research
Description© 2020 The Authors. Published by BMJ. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: http://dx.doi.org/10.1136/bmjresp-2020-000714
SponsorsGenetic analysis was supported by grants from the NIH NHLBI K08 HL118128 and R01 HL142992. SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C), and a grant from the NIH/ NHLBI (U01 HL137880, and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals; Chiesi Farmaceutici S.p.A.; Forest Research Institute; GlaxoSmithKline; Grifols Therapeutics; Ikaria; Novartis Pharmaceuticals Corporation; Nycomed GmbH; ProterixBio; Regeneron Pharmaceuticals; Sanofi; Sunovion; Takeda Pharmaceutical Company; and Theravance Biopharma and Mylan. IA was supported by a Wellcome Trust grant# 093080/Z/10/Z, EPSRC (EP/T003189/1) and by the UK MRC (MR/ T010371/1 and G1001367/1). PK was supported by a COPDMAP grant from the UK MRC (G1001367/1). EB and AH were supported by a grant from the British Lung Foundation (COPD10/7).
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by-nc/4.0/