title: Persistent mechanical stretch-induced calcium overload and MAPK signal activation contributed to SCF reduction in colonic smooth muscle in vivo and in vitro.
abstract: Gastrointestinal (GI) distention is a common pathological characteristic in most GI motility disorders (GMDs), however, their detail mechanism remains unknown. In this study, we focused on Ca2+overload of smooth muscle, which is an early intracellular reaction to stretch, and its downstream MAPK signaling and also reduction of SCF in vivo and in vitro. We successfully established colonic dilation mouse model by keeping incomplete colon obstruction for 8 days. The results showed that persistent colonic dilation clearly induced Ca2+overload and activated all the three MAPK family members including JNK, ERK and p38 in smooth muscle tissues. Similar results were obtained from dilated colon of patients with Hirschsprung's disease and stretched primary mouse colonic smooth muscle cells (SMCs). Furthermore, we demonstrated that persistent stretch-induced Ca2+overload was originated from extracellular Ca2+influx and endoplasmic reticulum (ER) Ca2+release identified by treating with different Ca2+channel blockers, and was responsible for the persistent activation of MAPK signaling and SCF reduction in colonic SMCs. Our results suggested that Ca2+overload caused by smooth muscle stretch led to persistent activation of MAPK signaling which might contribute to the decrease of SCF and development of the GMDs.
authors.affiliation: a Department of Histology and Embryology, School of Basic Medical Sciences , Capital Medical University , Beijing , P. R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Dong
authors.affiliation: a Department of Histology and Embryology, School of Basic Medical Sciences , Capital Medical University , Beijing , P. R. China.|b Beijing Key Laboratory of Cancer Invasion and Metastasis Research , Beijing , P. R. China.
authors.forename: Shu
authors.initials: S
authors.lastname: Yang
authors.affiliation: a Department of Histology and Embryology, School of Basic Medical Sciences , Capital Medical University , Beijing , P. R. China.|b Beijing Key Laboratory of Cancer Invasion and Metastasis Research , Beijing , P. R. China.
authors.forename: Haimei
authors.initials: H
authors.lastname: Sun
authors.affiliation: a Department of Histology and Embryology, School of Basic Medical Sciences , Capital Medical University , Beijing , P. R. China.
authors.forename: Jihong
authors.initials: J
authors.lastname: Yan
authors.affiliation: c Experimental Teaching Center of Preclinical Medicine , Capital Medical University , Beijing , P. R. China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Guo
authors.affiliation: a Department of Histology and Embryology, School of Basic Medical Sciences , Capital Medical University , Beijing , P. R. China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Li
authors.affiliation: a Department of Histology and Embryology, School of Basic Medical Sciences , Capital Medical University , Beijing , P. R. China.|b Beijing Key Laboratory of Cancer Invasion and Metastasis Research , Beijing , P. R. China.
authors.forename: Deshan
authors.initials: D
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics; D003106:Colon / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D015154:Esophageal Motility Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005769:Gastrointestinal Motility / Q000502:physiology; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000503:physiopathology; D006627:Hirschsprung Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D056885:Interstitial Cells of Cajal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D002118:Calcium
keywords: Calcium overload; MAPK signaling; colonic smooth muscle; gastrointestinal motility disorder; interstitial cell of Cajal