title: Heme oxygenase-1 upregulation modulates tone and fibroelastic properties of internal anal sphincter.
abstract: A compromise in the internal anal sphincter (IAS) tone and fibroelastic properties (FEP) plays an important role in rectoanal incontinence. Herein, we examined the effects of heme oxygenase (HO)-1 upregulation on these IAS characteristics in young rats. We determined the effect of HO-1 upregulator hemin on HO-1 mRNA and protein expressions and on basal IAS tone and its FEP before and after HO-1 inhibitor tin protoporphyrin IX. For FEP, we determined the kinetics of the IAS smooth muscle responses, by the velocities of relaxation, and recovery of the IAS tone following 0 Ca(2+) and electrical field stimulation. To characterize the underlying signal transduction for these changes, we determined the effects of hemin on RhoA-associated kinase (RhoA)/Rho kinase (ROCK) II, myosin-binding subunit of myosin light chain phosphatase 1, fibronectin, and elastin expression levels. Hemin increased HO-1 mRNA and protein similar to the increases in the basal tone, and in the FEP of the IAS. Underlying mechanisms in the IAS characteristics are associated with increases in the genetic and translational expressions of RhoA/ROCKII, and elastin. Fibronectin expression levels on the other hand were found to be decreased following HO-1 upregulation. The results of our study show that the hemin/HO-1 system regulates the tone and FEP of IAS. The hemin/HO-1 system thus provides a potential target for the development of new interventions aimed at treatment of gastrointestinal motility disorders, specifically the age-related IAS dysfunction.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Chadalavada Vijay
authors.initials: CV
authors.lastname: Krishna
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Jagmohan
authors.initials: J
authors.lastname: Singh
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Sumit
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania satish.rattan@jefferson.edu.
authors.forename: Satish
authors.initials: S
authors.lastname: Rattan
mesh_terms: D000367:Age Factors; D001003:Anal Canal / Q000187:drug effects / Q000201:enzymology* / Q000294:innervation; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004548:Elasticity; D004549:Elastin / Q000235:genetics / Q000378:metabolism; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D015854:Up-Regulation; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D005353:Fibronectins; D008665:Metalloporphyrins; D011524:Protoporphyrins; D012333:RNA, Messenger; D006427:Hemin; D004549:Elastin; C032628:tin protoporphyrin IX; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; C580818:ROCK2 protein, rat; D054460:rho-Associated Kinases; C499850:Ppp1r12a protein, rat; D054645:Protein Phosphatase 1; D002118:Calcium
keywords: rectoanal incontinence; smooth muscle tone