Arullampalam, Prakash; Essers, Maria C; Boukenna, Mey; Guichard, Sabrina; Rougier, Jean-Sébastien; Abriel, Hugues (2023). Knockdown of the TRPM4 channel alters cardiac electrophysiology and hemodynamics in a sex- and age-dependent manner in mice. Physiological reports, 11(16), e15783. The American Physiological Society 10.14814/phy2.15783
|
Text
Physiological_Reports_-_2023_-_Arullampalam.pdf - Published Version Available under License Creative Commons: Attribution (CC-BY). Download (7MB) | Preview |
TRPM4 is a calcium-activated, voltage-modulated, nonselective ion channel widely expressed in various cells and tissues. TRPM4 regulates the influx of sodium ions, thus playing a role in regulating the membrane potential. In the heart, TRPM4 is expressed in both cardiomyocytes and cells of the conductive pathways. Clinical studies have linked TRPM4 mutations to several cardiac disorders. While data from experimental studies have demonstrated TRPM4's functional significance in cardiac physiology, its exact roles in the heart have remained unclear. In this study, we investigated the role of TRPM4 in cardiac physiology in a newly generated Trpm4 knockdown mouse model. Male and female Trpm4 knockdown (Trpm4-/- ) and wild-type mice of different ages (5- to 12- week-old (young) and 24-week-old or more (adult)) were characterized using a multimodal approach, encompassing surface electrocardiograms (ECG), echocardiography recordings, ex vivo ECGs in isolated heart, endocardial mappings, Western blots, and mRNA quantifications. The assessment of cardiac electrophysiology by surface ECGs revealed no significant differences between wild-type and Trpm4-/- young (5- to 12-week-old) mice of either sex. Above 24 weeks of age, adult male Trpm4-/- mice showed reduced heart rate and increased heart rate variability. Echocardiography revealed that only adult male Trpm4-/- mice exhibited slight left ventricular hypertrophic alterations compared to controls, illustrated by alterations of the mitral valve pressure halftime, the mitral valve E/A ratio, the isovolumetric relaxation time, and the mitral valve deceleration. In addition, an assessment of the right ventricular systolic function by scanning the pulmonary valve highlighted an alteration in pulmonary valve peak velocity and pressure in adult male Trpm4-/- mice. Endocardial mapping recordings showed that applying 5 μM of the new TRPM4 inhibitor NBA triggered a third-degree atrioventricular block on 40% of wild-type hearts. These results confirm the key role of TRPM4 in the proper structure and electrical function of the heart. It also reveals differences between male and female animals that have never been reported. In addition, the investigation of the effects of NBA on heart function confirms the role of TRPM4 in atrioventricular conduction.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine |
UniBE Contributor: |
Arullampalam, Prakash, Essers, Maria Cristina, Boukenna, Mey, Guichard, Sabrina Lucienne Anny |
Subjects: |
500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health |
ISSN: |
2051-817X |
Publisher: |
The American Physiological Society |
Funders: |
[UNSPECIFIED] The National Centres of Competence in Research (NCCR) TransCure ; [UNSPECIFIED] The Swiss National Science Foundation |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
23 Aug 2023 16:32 |
Last Modified: |
24 Sep 2023 02:28 |
Publisher DOI: |
10.14814/phy2.15783 |
PubMed ID: |
37604672 |
Uncontrolled Keywords: |
TRPM4 channels cardiac physiology murine knockdown model |
BORIS DOI: |
10.48350/185637 |
URI: |
https://boris.unibe.ch/id/eprint/185637 |
Actions (login required)
 |
Edit item |