title: Mechanical stretch upregulates proteins involved in Ca2+ sensitization in urinary bladder smooth muscle hypertrophy.
abstract: Partial bladder outlet obstruction (pBOO)-induced remodeling of bladder detrusor smooth muscle (DSM) is associated with the modulation of cell signals regulating contraction. We analyzed the DSM from obstructed murine urinary bladders for the temporal regulation of RhoA GTPase and Rho-activated kinase (ROCK), which are linked to Ca(2+) sensitization. In addition, the effects of equibiaxial cell stretch, a condition thought to be associated with pBOO-induced bladder wall smooth muscle hypertrophy and voiding frequency, on the expression of RhoA, ROCK, and C-kinase-activated protein phosphatase I inhibitor (CPI-17) were investigated. DSM from 1-, 3-, 7-, and 14-day obstructed male mice bladders and benign prostatic hyperplasia (BPH)-induced obstructed human bladders revealed overexpression of RhoA and ROCK-β at the mRNA and protein levels compared with control. Primary human bladder myocytes seeded onto type I collagen-coated elastic silicone membranes were subjected to cyclic equibiaxial stretch, mimicking the cellular mechanical stretch in the bladder in vivo, and analyzed for the expression of RhoA, ROCK-β, and CPI-17. Stretch caused a significant increase of RhoA, ROCKβ, and CPI-17 expression. The stretch-induced increase in CPI-17 expression occurs at the transcriptional level and is associated with CPI-17 promoter binding by GATA-6 and NF-κB, the transcription factors responsible for CPI-17 gene transcription. Cell stretch caused by bladder overdistension in pBOO is the likely mechanism for initiating overexpression of the signaling proteins regulating DSM tone.
authors.affiliation: Division of Urology, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania;
authors.forename: Ettickan
authors.initials: E
authors.lastname: Boopathi
authors.affiliation: Hospital das Clinicas, University of Sao Paulo School of Medicine, Sao Paulo, Brazil;
authors.forename: Cristiano
authors.initials: C
authors.lastname: Gomes
authors.affiliation: Department of Urology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Zderic
authors.affiliation: Division of Urology, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania;
authors.forename: Bruce
authors.initials: B
authors.lastname: Malkowicz
authors.affiliation: Division of Urology, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania;
authors.forename: Ranjita
authors.initials: R
authors.lastname: Chakrabarti
authors.affiliation: Division of Urology, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania;
authors.forename: Darshan P
authors.initials: DP
authors.lastname: Patel
authors.affiliation: Division of Urology, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania;
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Wein
authors.affiliation: Division of Urology, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; chackosk@vet.upenn.edu.
authors.forename: Samuel
authors.initials: S
authors.lastname: Chacko
mesh_terms: D000368:Aged; D000818:Animals; D001665:Binding Sites; D020013:Calcium Signaling; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D050993:GATA6 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D006984:Hypertrophy; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D040542:Mechanotransduction, Cellular; D051379:Mice; D008875:Middle Aged; D009119:Muscle Contraction; D009124:Muscle Proteins; D009130:Muscle, Smooth / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011470:Prostatic Hyperplasia / Q000150:complications; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D001743:Urinary Bladder / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001748:Urinary Bladder Neck Obstruction / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D016328:NF-kappa B; C107507:PPP1R14A protein, human; D012333:RNA, Messenger; C066737:RHOA protein, human; D054460:rho-Associated Kinases; D010749:Phosphoprotein Phosphatases; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
keywords: benign prostatic hyperplasia; calcium sensitization; cell stretch; human bladder; partial bladder outlet obstruction