Cellular mechanism of mechanotranscription in colonic smooth muscle cells

Feng Li, You Min Lin, Sushil K. Sarna, Xuan-Zheng Shi

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Mechanical stretch in obstruction induces expression of cyclooxygenase-2 (COX-2) in gut smooth muscle cells (SMCs). The stretch-induced COX-2 plays a critical role in motility dysfunction in obstructive bowel disorders (OBDs). The aims of the present study were to investigate the intracellular mechanism of mechanotranscription of COX-2 in colonic SMCs and to determine whether inhibition of mechanotranscription has therapeutic benefits in OBDs. Static stretch was mimicked in vitro in primary culture of rat colonic circular SMCs (RCCSMCs) and in colonic circular muscle strips. Partial obstruction was surgically induced with a silicon band in the distal colon of rats and COX-2-deficient mice. Static stretch of RCCSMCs significantly induced expression of COX-2 mRNA and protein and activated MAP kinases ERKs, p38, and JNKs. ERKs inhibitor PD98059, p38 inhibitor SB203580, and JNKs inhibitor SP600125 significantly blocked stretch-induced COX-2 expression. Pharmacological and molecular inhibition of stretch-activated ion channels (SACs) and integrins significantly suppressed stretchinduced expression of COX-2. SAC blockers inhibited stretchactivated ERKs, p38, and JNKs, but inhibition of integrins attenuated p38 activation only. In colonic circular muscle strips, stretch led to activation of MAPKs, induction of COX-2, and suppression of contractility. Inhibition of p38 with SB203580 blocked COX-2 expression and restored muscle contractility. Administration of SB203580 in vivo inhibited obstruction-induced COX-2 and improved motility function. Stretch-induced expression of COX-2 in RCCSMCs depends on mechanosensors, SACs, and integrins and an intracellular signaling mechanism involving MAPKs ERKs, p38, and JNKs. Inhibitors of the mechanotranscription pathway have therapeutic potentials for OBDs.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume303
Issue number5
DOIs
StatePublished - Sep 1 2012

Fingerprint

Cyclooxygenase 2
Smooth Muscle Myocytes
Ion Channels
Integrins
p38 Mitogen-Activated Protein Kinases
Muscles
Silicon
Colon
Pharmacology
Messenger RNA

Keywords

  • Cyclooxygenase-2
  • Integrin
  • Mechanical stretch
  • Mitogen-activated protein kinase
  • Stretch-activated ion channel

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

Cellular mechanism of mechanotranscription in colonic smooth muscle cells. / Li, Feng; Lin, You Min; Sarna, Sushil K.; Shi, Xuan-Zheng.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 303, No. 5, 01.09.2012.

Research output: Contribution to journalArticle

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