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

Shibo Fu, Moses T. Tar, Arnold Melman, Kelvin Davies

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 - 2014

Fingerprint

glutaminyl-arginyl-phenylalanyl-seryl-arginine
Smooth Muscle Myocytes
Muscle
Adenosine A2B Receptors
Cells
Priapism
Sickle Cell Anemia
Up-Regulation
Small Interfering RNA
Smooth Muscle
Rats
Oxygen
Gene expression
Gene Expression
Hypoxia
Animals
Genes
Chemical activation

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Opiorphin is a master regulator of the hypoxic response in corporal smooth muscle cells. / Fu, Shibo; Tar, Moses T.; Melman, Arnold; Davies, Kelvin.

In: FASEB Journal, Vol. 28, No. 8, 2014, p. 3633-3644.

Research output: Contribution to journalArticle

@article{36f58207285345698284cb2cd0aa6e3c,
title = "Opiorphin is a master regulator of the hypoxic response in corporal smooth muscle cells",
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.",
keywords = "A2B-adenosine receptor, Hypoxia inducible factor-1a, Priapism, Sialorphin, Sickle cell disease",
author = "Shibo Fu and Tar, {Moses T.} and Arnold Melman and Kelvin Davies",
year = "2014",
doi = "10.1096/fj.13-248708",
language = "English (US)",
volume = "28",
pages = "3633--3644",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "8",

}

TY - JOUR

T1 - Opiorphin is a master regulator of the hypoxic response in corporal smooth muscle cells

AU - Fu, Shibo

AU - Tar, Moses T.

AU - Melman, Arnold

AU - Davies, Kelvin

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - A2B-adenosine receptor

KW - Hypoxia inducible factor-1a

KW - Priapism

KW - Sialorphin

KW - Sickle cell disease

UR - http://www.scopus.com/inward/record.url?scp=84905270105&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905270105&partnerID=8YFLogxK

U2 - 10.1096/fj.13-248708

DO - 10.1096/fj.13-248708

M3 - Article

C2 - 24803544

AN - SCOPUS:84905270105

VL - 28

SP - 3633

EP - 3644

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 8

ER -