Cellular mechanism of mechanotranscription in colonic smooth muscle cells.
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 stretch-induced expression of COX-2. SAC blockers inhibited stretch-activated 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.
Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, 77555-0655, USA.
Feng
F
Li
You-Min
YM
Lin
Sushil K
SK
Sarna
Xuan-Zheng
XZ
Shi
D000818:Animals; D015153:Blotting, Western; D003106:Colon / Q000166:cytology / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D016023:Integrins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D009470:Muscle Spindles / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D016023:Integrins; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat