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

FASEB J. 2014 Aug;28(8):3633-44. doi: 10.1096/fj.13-248708. Epub 2014 May 6.


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. Sialorphin-treated 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-up-regulation 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.

Keywords: A2B-adenosine receptor; hypoxia inducible factor-1a; priapism; sialorphin; sickle cell disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anemia, Sickle Cell / complications*
  • Anemia, Sickle Cell / metabolism
  • Animals
  • Cell Hypoxia / physiology*
  • Cells, Cultured
  • Cobalt / pharmacology
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, SCID
  • Myocytes, Smooth Muscle / physiology*
  • Penis / cytology*
  • Penis / growth & development
  • Priapism / etiology
  • Priapism / physiopathology*
  • Protein Precursors / pharmacology
  • Protein Precursors / physiology*
  • RNA Interference
  • RNA, Small Interfering / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Adenosine A2B / biosynthesis
  • Receptor, Adenosine A2B / genetics
  • Salivary Proteins and Peptides / biosynthesis
  • Salivary Proteins and Peptides / genetics
  • Salivary Proteins and Peptides / pharmacology
  • Salivary Proteins and Peptides / physiology*
  • Up-Regulation / drug effects


  • Hif1a protein, mouse
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Protein Precursors
  • RNA, Small Interfering
  • Receptor, Adenosine A2B
  • Salivary Proteins and Peptides
  • Smr2 protein, mouse
  • Smr3a protein, mouse
  • Smr3b protein, rat
  • Cobalt
  • cobaltous chloride