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

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• 作者：Marco Piccoli^a ; ¹ ; Erika Conforti^a ; ¹ ; Alessandro Varrica^a ; Andrea Ghiroldi^a ; Federica Cirillo^a ; Giulia Resmini^a ; Francesca Pluchinotta^a ; Guido Tettamanti^a ; Alessandro Giamberti^a ; Alessandro Frigiola^a ; Luigi Anastasia^a ; ^b ; ^{luigi.anastasia@unimi.it}
• 关键词：HIF-1α ; Sialidase NEU3 ; Congenital heart defects ; Chronic hypoxia ; EGFR signaling pathway
• 刊名：International Journal of Cardiology
• 出版年：2017
• 出版时间：1 March 2017
• 年：2017
• 卷：230
• 期：Complete
• 页码：6-13
• 全文大小：1284 K
• 卷排序：230

文摘

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.MethodsRight 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.ResultsCyanotic 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.ConclusionsSialidase 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.