Excess adenosine A2B receptor signaling contributes to priapism through HIF-1α mediated reduction of PDE5 gene expression.

Abstract

Priapism is featured with prolonged and painful penile erection and is prevalent among males with sickle cell disease (SCD). The disorder is a dangerous urological and hematological emergency since it is associated with ischemic tissue damage and erectile disability. Here we report that phosphodiesterase-5 (PDE5) gene expression and PDE activity is significantly reduced in penile tissues of two independent priapic models: SCD mice and adenosine deaminase (ADA)-deficient mice. Moreover, using ADA enzyme therapy to reduce adenosine or a specific antagonist to block A(2B) adenosine receptor (ADORA2B) signaling, we successfully attenuated priapism in both ADA(-/-) and SCD mice by restoring penile PDE5 gene expression to normal levels. This finding led us to further discover that excess adenosine signaling via ADORA2B activation directly reduces PDE5 gene expression in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. Overall, we reveal that excess adenosine-mediated ADORA2B signaling underlies reduced penile PDE activity by decreasing PDE5 gene expression in a HIF-1α-dependent manner and provide new insight for the pathogenesis of priapism and novel therapies for the disease.

• Authors: Chen Ning, Jiaming Wen, Yujin Zhang, Yingbo Dai, Wei Wang, Weiru Zhang, Lin Qi, Almut Grenz, Holger K Eltzschig, Michael R Blackburn, Rodney E Kellems, Yang Xia
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 28 Issue 6 Pg. 2725-35 (Jun 2014) ISSN: 1530-6860 [Electronic] United States
• PMID: 24614760 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © FASEB.

Chemical References

• 1-propyl-8-(4-sulfophenyl)xanthine
• Adenosine A2 Receptor Antagonists
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Receptor, Adenosine A2B
• Xanthines
• Cyclic Nucleotide Phosphodiesterases, Type 5
• Pde5a protein, mouse
• Adenosine Deaminase
• pegademase bovine

Topics

• Adenosine A2 Receptor Antagonists (pharmacology)
• Adenosine Deaminase (deficiency, therapeutic use)
• Agammaglobulinemia (drug therapy)
• Animals
• Cyclic Nucleotide Phosphodiesterases, Type 5 (genetics, metabolism)
• Gene Expression
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Male
• Mice
• Mice, SCID
• Mice, Transgenic
• Penile Erection (drug effects)
• Penis (metabolism)
• Priapism (drug therapy, etiology, metabolism)
• Receptor, Adenosine A2B (metabolism)
• Severe Combined Immunodeficiency (drug therapy)
• Signal Transduction (physiology)
• Xanthines (therapeutic use)