RGD Reference Report - Characterization of Kcnk3-Mutated Rat, a Novel Model of Pulmonary Hypertension. - Rat Genome Database

Send us a Message

Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   

Characterization of Kcnk3-Mutated Rat, a Novel Model of Pulmonary Hypertension.

Authors: Lambert, Mélanie  Capuano, Véronique  Boet, Angèle  Tesson, Laurent  Bertero, Thomas  Nakhleh, Morad K  Remy, Séverine  Anegon, Ignacio  Pechoux, Christine  Hautefort, Aurélie  Rucker-Martin, Catherine  Manoury, Boris  Domergue, Valérie  Mercier, Olaf  Girerd, Barbara  Montani, David  Perros, Frédéric  Humbert, Marc  Antigny, Fabrice 
Citation: Lambert M, etal., Circ Res. 2019 Sep 13;125(7):678-695. doi: 10.1161/CIRCRESAHA.119.314793. Epub 2019 Jul 26.
RGD ID: 151347452
Pubmed: (View Article at PubMed) PMID:31347976
DOI: Full-text: DOI:10.1161/CIRCRESAHA.119.314793

RATIONALE: Pulmonary arterial hypertension is a severe lethal cardiopulmonary disease. Loss of function mutations in KCNK3 (potassium channel subfamily K member 3) gene, which encodes an outward rectifier K+ channel, have been identified in pulmonary arterial hypertension patients.
OBJECTIVE: We have demonstrated that KCNK3 dysfunction is common to heritable and nonheritable pulmonary arterial hypertension and to experimental pulmonary hypertension (PH). Finally, KCNK3 is not functional in mouse pulmonary vasculature.
METHODS AND RESULTS: Using CRISPR/Cas9 technology, we generated a 94 bp out of frame deletion in exon 1 of Kcnk3 gene and characterized these rats at the electrophysiological, echocardiographic, hemodynamic, morphological, cellular, and molecular levels to decipher the cellular mechanisms associated with loss of KCNK3. Using patch-clamp technique, we validated our transgenic strategy by demonstrating the absence of KCNK3 current in freshly isolated pulmonary arterial smooth muscle cells from Kcnk3-mutated rats. At 4 months of age, echocardiographic parameters revealed shortening of the pulmonary artery acceleration time associated with elevation of the right ventricular systolic pressure. Kcnk3-mutated rats developed more severe PH than wild-type rats after monocrotaline exposure or chronic hypoxia exposure. Kcnk3-mutation induced a lung distal neomuscularization and perivascular extracellular matrix activation. Lungs of Kcnk3-mutated rats were characterized by overactivation of ERK1/2 (extracellular signal-regulated kinase1-/2), AKT (protein kinase B), SRC, and overexpression of HIF1-α (hypoxia-inducible factor-1 α), survivin, and VWF (Von Willebrand factor). Linked with plasma membrane depolarization, reduced endothelial-NOS expression and desensitization of endothelial-derived hyperpolarizing factor, Kcnk3-mutated rats presented predisposition to vasoconstriction of pulmonary arteries and a severe loss of sildenafil-induced pulmonary arteries relaxation. Moreover, we showed strong alteration of right ventricular cardiomyocyte excitability. Finally, Kcnk3-mutated rats developed age-dependent PH associated with low serum-albumin concentration.
CONCLUSIONS: We established the first Kcnk3-mutated rat model of PH. Our results confirm that KCNK3 loss of function is a key event in pulmonary arterial hypertension pathogenesis. This model presents new opportunities for understanding the initiating mechanisms of PH and testing biologically relevant therapeutic molecules in the context of PH.

Disease Annotations    

Gene Ontology Annotations    

Biological Process

Phenotype Annotations    
Objects Annotated

Genes (Rattus norvegicus)
Kcnk3  (potassium two pore domain channel subfamily K member 3)
Kcnk3em1Ang  (potassium two pore domain channel subfamily K member 3; CRISPR/Cas9 induced mutant1, Ang)

Genes (Mus musculus)
Kcnk3  (potassium channel, subfamily K, member 3)

Genes (Homo sapiens)
KCNK3  (potassium two pore domain channel subfamily K member 3)

Additional Information