NEU3 sialidase role in activating HIF-1α in response to chronic hypoxia in cyanotic congenital heart patients

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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.

Original languageEnglish
Pages (from-to)6-13
Number of pages8
JournalInternational Journal of Cardiology
Volume230
DOIs
Publication statusPublished - Mar 1 2017

Fingerprint

Hypoxia-Inducible Factor 1
Neuraminidase
Congenital Heart Defects
Atrial Appendage
Hypoxia
Real-Time Polymerase Chain Reaction
Proteins
Up-Regulation
Western Blotting
Phosphorylation
Pediatrics
Pathology
Biopsy
Messenger RNA

Keywords

  • Chronic hypoxia
  • Congenital heart defects
  • EGFR signaling pathway
  • HIF-1α
  • Sialidase NEU3

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

@article{51346d7d257d4184b2d2009ce56a26f2,
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.",
keywords = "Chronic hypoxia, Congenital heart defects, EGFR signaling pathway, HIF-1α, Sialidase NEU3",
author = "Marco Piccoli and Erika Conforti and Alessandro Varrica and Andrea Ghiroldi and Federica Cirillo and Giulia Resmini and Francesca Pluchinotta and Guido Tettamanti and Alessandro Giamberti and Alessandro Frigiola and Luigi Anastasia",
year = "2017",
month = "3",
day = "1",
doi = "10.1016/j.ijcard.2016.12.123",
language = "English",
volume = "230",
pages = "6--13",
journal = "International Journal of Cardiology",
issn = "0167-5273",
publisher = "Elsevier Ireland Ltd",

}

TY - JOUR

T1 - NEU3 sialidase role in activating HIF-1α in response to chronic hypoxia in cyanotic congenital heart patients

AU - Piccoli, Marco

AU - Conforti, Erika

AU - Varrica, Alessandro

AU - Ghiroldi, Andrea

AU - Cirillo, Federica

AU - Resmini, Giulia

AU - Pluchinotta, Francesca

AU - Tettamanti, Guido

AU - Giamberti, Alessandro

AU - Frigiola, Alessandro

AU - Anastasia, Luigi

PY - 2017/3/1

Y1 - 2017/3/1

N2 - 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.

AB - 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.

KW - Chronic hypoxia

KW - Congenital heart defects

KW - EGFR signaling pathway

KW - HIF-1α

KW - Sialidase NEU3

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U2 - 10.1016/j.ijcard.2016.12.123

DO - 10.1016/j.ijcard.2016.12.123

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VL - 230

SP - 6

EP - 13

JO - International Journal of Cardiology

JF - International Journal of Cardiology

SN - 0167-5273

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