title: 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.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas, USA; Department of Urology and Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China;
authors.forename: Chen
authors.initials: C
authors.lastname: Ning
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas, USA; Second Affiliated Hospital, Zhejiang University, Hangzhou, China;
authors.forename: Jiaming
authors.initials: J
authors.lastname: Wen
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas, USA;
authors.forename: Yujin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas, USA; Department of Urology and.
authors.forename: Yingbo
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas, USA; Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China;
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas, USA; Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China;
authors.forename: Weiru
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Urology and.
authors.forename: Lin
authors.initials: L
authors.lastname: Qi
authors.affiliation: Department of Anesthesiology, The University of Colorado School of Medicine, Denver, Colorado, USA; and.
authors.forename: Almut
authors.initials: A
authors.lastname: Grenz
authors.affiliation: Department of Anesthesiology, The University of Colorado School of Medicine, Denver, Colorado, USA; and.
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas, USA; Graduate School of Biomedical Science, The University of Texas, Houston, Texas, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas, USA; Graduate School of Biomedical Science, The University of Texas, Houston, Texas, USA.
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Kellems
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas, USA; Second Affiliated Hospital, Zhejiang University, Hangzhou, China; Graduate School of Biomedical Science, The University of Texas, Houston, Texas, USA yang.xia@uth.tmc.edu.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000172:deficiency / Q000627:therapeutic use; D000361:Agammaglobulinemia / Q000188:drug therapy; D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D010410:Penile Erection / Q000187:drug effects; D010413:Penis / Q000378:metabolism; D011317:Priapism / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000378:metabolism*; D016511:Severe Combined Immunodeficiency / Q000188:drug therapy; D015398:Signal Transduction / Q000502:physiology; D014970:Xanthines / Q000627:therapeutic use
chemical_list: C518874:1-propyl-8-(4-sulfophenyl)xanthine; D058917:Adenosine A2 Receptor Antagonists; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D043704:Receptor, Adenosine A2B; D014970:Xanthines; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse; D000243:Adenosine Deaminase; C051409:pegademase bovine
keywords: hypoxia-inducible factor; phosphodiesterase-5; sickle cell disease