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Loss of KCNK3 is a hallmark of RV hypertrophy/dysfunction associated with pulmonary hypertension
- Source :
- Cardiovascular research. 114(6)
- Publication Year :
- 2017
-
Abstract
- Aims Mutations in the KCNK3 gene, which encodes for an outward-rectifier K+ channel, have been identified in patients suffering from pulmonary arterial hypertension (PAH), and constitute the first described channelopathy in PAH. In human PAH and experimental pulmonary hypertension (PH), we demonstrated that KCNK3 expression and function are severely reduced in pulmonary vascular cells, promoting PH-like phenotype at the morphologic and haemodynamic levels. Since KCNK3 channel is also expressed in both the human and rodent heart, we aimed to elucidate the pathophysiological role of KCNK3 channel in right ventricular (RV) hypertrophy (RVH) related to PH. Methods and results Using whole-cell Patch-clamp technique, we demonstrated that KCNK3 is predominantly expressed in adult rat RV cardiomyocytes compared to the left ventricle cardiomyocytes and participates in the repolarizing phase of the RV action potential. We revealed a reduction in KCNK3 function prior to development of RVH and the rise of pulmonary vascular resistance. KCNK3 function is severely reduced in RV cardiomyocytes during the development of RVH in several rat models of PH (exposure to monocrotaline, chronic hypoxia, and Sugen/hypoxia) and chronic RV pressure overload (pulmonary artery banding). In experimental PH, we revealed a reduction in KCNK3 function before any rise in pulmonary vascular resistance and the development of RVH. KCNK3 mRNA level is also reduced in human RV tissues from PAH patients compared to non-PAH patients. In line with these findings, chronic inhibition of KCNK3 in rats with the specific inhibitor (A293) induces RV hypertrophy which is associated with the re-expression of foetal genes, RV fibrosis, RV inflammation, and subsequent loss of RV performance as assessed by echocardiography. Conclusion Our data indicate that loss of KCNK3 function and expression is a hallmark of the RV hypertrophy/dysfunction associated with PH.
- Subjects :
- 0301 basic medicine
Male
Time Factors
Physiology
Ventricular Dysfunction, Right
Action Potentials
030204 cardiovascular system & hematology
Pulmonary artery banding
Muscle hypertrophy
0302 clinical medicine
Fibrosis
Myocytes, Cardiac
ortho-Aminobenzoates
Sulfonamides
Ventricular Remodeling
Middle Aged
medicine.anatomical_structure
Cardiology
Female
medicine.symptom
Cardiology and Cardiovascular Medicine
Signal Transduction
Adult
medicine.medical_specialty
Adolescent
Hypertension, Pulmonary
Down-Regulation
Nerve Tissue Proteins
03 medical and health sciences
Potassium Channels, Tandem Pore Domain
Physiology (medical)
Internal medicine
medicine
Potassium Channel Blockers
Animals
Humans
Pressure overload
Hypertrophy, Right Ventricular
business.industry
Hypoxia (medical)
medicine.disease
Pulmonary hypertension
Rats
Disease Models, Animal
030104 developmental biology
Ventricle
Case-Control Studies
Vascular resistance
Ventricular Function, Right
business
Subjects
Details
- ISSN :
- 17553245
- Volume :
- 114
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Cardiovascular research
- Accession number :
- edsair.doi.dedup.....81ef7305cbdc772650f73c372e67c886