RGD Reference Report - An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure. - Rat Genome Database

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An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure.

Authors: Thorneloe, KS  Cheung, M  Bao, W  Alsaid, H  Lenhard, S  Jian, MY  Costell, M  Maniscalco-Hauk, K  Krawiec, JA  Olzinski, A  Gordon, E  Lozinskaya, I  Elefante, L  Qin, P  Matasic, DS  James, C  Tunstead, J  Donovan, B  Kallal, L  Waszkiewicz, A  Vaidya, K  Davenport, EA  Larkin, J  Burgert, M  Casillas, LN  Marquis, RW  Ye, G  Eidam, HS  Goodman, KB  Toomey, JR  Roethke, TJ  Jucker, BM  Schnackenberg, CG  Townsley, MI  Lepore, JJ  Willette, RN 
Citation: Thorneloe KS, etal., Sci Transl Med. 2012 Nov 7;4(159):159ra148. doi: 10.1126/scitranslmed.3004276.
RGD ID: 10400856
Pubmed: PMID:23136043   (View Abstract at PubMed)
DOI: DOI:10.1126/scitranslmed.3004276   (Journal Full-text)

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.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Trpv4Ratcalcium ion transmembrane transport involved_inIMP PMID:23136043UniProt 
Trpv4Ratmulticellular organismal-level water homeostasis involved_inIMP PMID:23136043UniProt 
Trpv4Ratpositive regulation of vascular permeability involved_inIMP PMID:23136043UniProt 
Trpv4Ratregulation of blood pressure NOT|involved_inIMP PMID:23136043UniProt 
Trpv4Ratregulation of heart rate NOT|involved_inIMP PMID:23136043UniProt 
Trpv4Ratregulation of response to osmotic stress NOT|involved_inIMP PMID:23136043UniProt 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Trpv4Ratcalcium channel activity enablesIMP PMID:23136043UniProt 

Objects Annotated

Genes (Rattus norvegicus)
Trpv4  (transient receptor potential cation channel, subfamily V, member 4)


Additional Information