title: NEU3 sialidase role in activating HIF-1α in response to chronic hypoxia in cyanotic congenital heart patients.
abstract: BACKGROUND
  Hypoxia is a common feature of many congenital heart defects (CHDs) and significantly contributes to their pathophysiology. Thus, understanding the mechanism underlying cell response to hypoxia is vital for the development of novel therapeutic strategies. Certainly, the hypoxia inducible factor (HIF) has been extensively investigated and it is now recognized as the master regulator of cell defense machinery counteracting hypoxic stress. Along this line, we recently discovered and reported a novel mechanism of HIF activation, which is mediated by sialidase NEU3. Thus, aim of this study was to test whether NEU3 played any role in the cardiac cell response to chronic hypoxia in congenital cyanotic patients.
  
  
  METHODS
  Right atrial appendage biopsies were obtained from pediatric patients with cyanotic/non-cyanotic CHDs and processed to obtain mRNA and proteins. Real-Time PCR and Western Blot were performed to analyze HIF-1α and its downstream targets expression, NEU3 expression, and the NEU3 mediated effects on the EGFR signaling cascade.
  
  
  RESULTS
  Cyanotic patients showed increased levels of HIF-1α, NEU3, EGFR and their downstream targets, as compared to acyanotic controls. The same patients were also characterized by increased phosphorylation of the EGFR signaling cascade proteins. Moreover, we found that HIF-1α expression levels positively correlated with those recorded for NEU3 in both cyanotic and control patients.
  
  
  CONCLUSIONS
  Sialidase NEU3 plays a central role in activating cell response to chronic hypoxia inducing the up-regulation of HIF-1α, and this represent a possible novel tool to treat several CHD pathologies.
authors.affiliation: Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Piazza Malan 2, 20097 San Donato Milanese, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Piccoli
authors.affiliation: Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Piazza Malan 2, 20097 San Donato Milanese, Milan, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Conforti
authors.affiliation: Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Piazza Malan 2, 20097 San Donato Milanese, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Varrica
authors.affiliation: Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Piazza Malan 2, 20097 San Donato Milanese, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ghiroldi
authors.affiliation: Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Piazza Malan 2, 20097 San Donato Milanese, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Cirillo
authors.affiliation: Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Piazza Malan 2, 20097 San Donato Milanese, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Resmini
authors.affiliation: Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Piazza Malan 2, 20097 San Donato Milanese, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pluchinotta
authors.affiliation: Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Piazza Malan 2, 20097 San Donato Milanese, Milan, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Tettamanti
authors.affiliation: Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Piazza Malan 2, 20097 San Donato Milanese, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Giamberti
authors.affiliation: Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Piazza Malan 2, 20097 San Donato Milanese, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Frigiola
authors.affiliation: Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Piazza Malan 2, 20097 San Donato Milanese, Milan, Italy; Department of Biomedical Sciences for Health, University of Milan, via Luigi Mangiagalli 31, 20133 Milan, Italy. Electronic address: luigi.anastasia@unimi.it.
authors.forename: Luigi
authors.initials: L
authors.lastname: Anastasia
mesh_terms: D016022:Case-Control Studies; D002675:Child, Preschool; D002908:Chronic Disease; D003490:Cyanosis / Q000150:complications / Q000378:metabolism*; D005260:Female; D006330:Heart Defects, Congenital / Q000150:complications* / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000209:etiology / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007223:Infant; D008297:Male; D009439:Neuraminidase / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C465436:Neu3 protein, human; D009439:Neuraminidase
keywords: Chronic hypoxia; Congenital heart defects; EGFR signaling pathway; HIF-1α; Sialidase NEU3