Opiorphin is a master regulator of the hypoxic response in corporal smooth muscle cells

Shibo Fu, Moses Tarndie Tar, Arnold Melman, Kelvin Paul Davies

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Men with sickle cell disease (SCD) risk developing priapism. Recognizing that SCD is a disease of hypoxia, we investigated the effect of hypoxia on gene expression in corporal smooth muscle (CSM) cells. Rat CSM cells in vitro were treated with CoCl2 or low oxygen tension to mimic hypoxia. Hypoxic conditions increased expression of genes previously associated with priapism in animal models. Variable coding sequence a1 (Vcsa1; the rat opiorphin homologue, sialorphin), hypoxia-inducible factor 1a (Hif-1a), and A2B adenosine receptor (a2br) were increased by 10-, 4-, and 6-fold, respectively, by treatment with CoCl2, whereas low oxygen tension caused increases in expression of 3-, 4-, and 1.5-fold, respectively. Sialorphintreated CSM cells increased expression of Hif-1a and a2br by 4-fold, and vcsa1-siRNA treatment reduced expression by ∼50%. Using a Hif-1a inhibitor, we demonstrated up-regulation of a2br by sialorphin is dependent on Hif-1a, and knockdown of vcsa1 expression with vcsa1-siRNA demonstrated that hypoxic-upregulation of Hif-1a is dependent on vcsa1. In CSM from a SCD mouse, there was 15-fold up-regulation of opiorphin at a life stage prior to priapism. We conclude that in CSM, opiorphins are master regulators of the hypoxic response. Opiorphin up-regulation in response to SCD-associated hypoxia activates CSM "relaxant"pathways; excessive activation of these pathways results in priapism.

Original languageEnglish (US)
Pages (from-to)3633-3644
Number of pages12
JournalFASEB Journal
Volume28
Issue number8
DOIs
StatePublished - Aug 2014

Keywords

  • A2B-adenosine receptor
  • Hypoxia inducible factor-1a
  • Priapism
  • Sialorphin
  • Sickle cell disease

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Fingerprint Dive into the research topics of 'Opiorphin is a master regulator of the hypoxic response in corporal smooth muscle cells'. Together they form a unique fingerprint.

  • Cite this