title: An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure.
abstract: Pulmonary edema resulting from high pulmonary venous pressure (PVP) is a major cause of morbidity and mortality in heart failure (HF) patients, but current treatment options demonstrate substantial limitations. Recent evidence from rodent lungs suggests that PVP-induced edema is driven by activation of pulmonary capillary endothelial transient receptor potential vanilloid 4 (TRPV4) channels. To examine the therapeutic potential of this mechanism, we evaluated TRPV4 expression in human congestive HF lungs and developed small-molecule TRPV4 channel blockers for testing in animal models of HF. TRPV4 immunolabeling of human lung sections demonstrated expression of TRPV4 in the pulmonary vasculature that was enhanced in sections from HF patients compared to controls. GSK2193874 was identified as a selective, orally active TRPV4 blocker that inhibits Ca(2+) influx through recombinant TRPV4 channels and native endothelial TRPV4 currents. In isolated rodent and canine lungs, TRPV4 blockade prevented the increased vascular permeability and resultant pulmonary edema associated with elevated PVP. Furthermore, in both acute and chronic HF models, GSK2193874 pretreatment inhibited the formation of pulmonary edema and enhanced arterial oxygenation. Finally, GSK2193874 treatment resolved pulmonary edema already established by myocardial infarction in mice. These findings identify a crucial role for TRPV4 in the formation of HF-induced pulmonary edema and suggest that TRPV4 blockade is a potential therapeutic strategy for HF patients.
authors.affiliation: Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapy Area Unit, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA. Kevin.S.Thorneloe@gsk.com
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Thorneloe
authors.forename: Mui
authors.initials: M
authors.lastname: Cheung
authors.forename: Weike
authors.initials: W
authors.lastname: Bao
authors.forename: Hasan
authors.initials: H
authors.lastname: Alsaid
authors.forename: Stephen
authors.initials: S
authors.lastname: Lenhard
authors.forename: Ming-Yuan
authors.initials: MY
authors.lastname: Jian
authors.forename: Melissa
authors.initials: M
authors.lastname: Costell
authors.forename: Kristeen
authors.initials: K
authors.lastname: Maniscalco-Hauk
authors.forename: John A
authors.initials: JA
authors.lastname: Krawiec
authors.forename: Alan
authors.initials: A
authors.lastname: Olzinski
authors.forename: Earl
authors.initials: E
authors.lastname: Gordon
authors.forename: Irina
authors.initials: I
authors.lastname: Lozinskaya
authors.forename: Lou
authors.initials: L
authors.lastname: Elefante
authors.forename: Pu
authors.initials: P
authors.lastname: Qin
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Matasic
authors.forename: Chris
authors.initials: C
authors.lastname: James
authors.forename: James
authors.initials: J
authors.lastname: Tunstead
authors.forename: Brian
authors.initials: B
authors.lastname: Donovan
authors.forename: Lorena
authors.initials: L
authors.lastname: Kallal
authors.forename: Anna
authors.initials: A
authors.lastname: Waszkiewicz
authors.forename: Kalindi
authors.initials: K
authors.lastname: Vaidya
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Davenport
authors.forename: Jonathan
authors.initials: J
authors.lastname: Larkin
authors.forename: Mark
authors.initials: M
authors.lastname: Burgert
authors.forename: Linda N
authors.initials: LN
authors.lastname: Casillas
authors.forename: Robert W
authors.initials: RW
authors.lastname: Marquis
authors.forename: Guosen
authors.initials: G
authors.lastname: Ye
authors.forename: Hilary S
authors.initials: HS
authors.lastname: Eidam
authors.forename: Krista B
authors.initials: KB
authors.lastname: Goodman
authors.forename: John R
authors.initials: JR
authors.lastname: Toomey
authors.forename: Theresa J
authors.initials: TJ
authors.lastname: Roethke
authors.forename: Beat M
authors.initials: BM
authors.lastname: Jucker
authors.forename: Christine G
authors.initials: CG
authors.lastname: Schnackenberg
authors.forename: Mary I
authors.initials: MI
authors.lastname: Townsley
authors.forename: John J
authors.initials: JJ
authors.lastname: Lepore
authors.forename: Robert N
authors.initials: RN
authors.lastname: Willette
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004232:Diuretics / Q000494:pharmacology; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006333:Heart Failure / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D049990:Membrane Transport Modulators / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011654:Pulmonary Edema / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014882:Water-Electrolyte Balance / Q000187:drug effects
chemical_list: D004232:Diuretics; D049990:Membrane Transport Modulators; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; C486576:Trpv4 protein, mouse; D002118:Calcium