TRPM4 modulates right ventricular remodeling under pressure load accompanied with decreased expression level
Background - Survival of patients with congenital heart defects including increased right ventricular pressure load (ie, tetralogy of Fallot) or pulmonary hypertension is dependent on the function of the right ventricle (RV). RV remodeling has several effects with progressive transition from compens...
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| Main Authors: | , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
6 March 2020
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| In: |
Journal of cardiac failure
Year: 2020, Volume: 26, Issue: 7, Pages: 599-609 |
| ISSN: | 1532-8414 |
| DOI: | 10.1016/j.cardfail.2020.02.006 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.cardfail.2020.02.006 Verlag, lizenzpflichtig, Volltext: http://www.sciencedirect.com/science/article/pii/S1071916419304403 
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| Author Notes: | Wiebke Frede, Rebekka Medert, PhD, Tanja Poth, MD, Matthias Gorenflo, MD, Rudi Vennekens, PhD, Marc Freichel, MD, and Stebastian Uhl, MD |
MARC
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| 520 | |a Background - Survival of patients with congenital heart defects including increased right ventricular pressure load (ie, tetralogy of Fallot) or pulmonary hypertension is dependent on the function of the right ventricle (RV). RV remodeling has several effects with progressive transition from compensated status to heart failure. Transient receptor potential melastatin 4 (TRPM4) forms cation channels expressed in myocardium, which was shown to modulate cardiac remodeling in the left ventricle of mice. Aim of this study was to identify the role of TRPM4 for contractile function and remodeling of the RV in a rat model of right ventricular pressure load. - Methods and Results - We performed experiments with untreated rats and under monocrotaline (MCT)-induced pressure load comparing wild-type (Trpm4+/+) and TRPM4-deficient (Trpm4−/−) rats. RV function was characterized by echocardiography and contractility measurements of isolated papillary muscles. RV hypertrophy was investigated by echocardiography and by determination of hypertrophy indices. Pulmonary arterial remodeling was evaluated by echocardiography and histology. TRPM4 protein expression in RV of human, rat and mouse was detected by Western blot and quantified in rat. TRPM4 proteins were detected in RV myocardium of rat and mouse, which were not detectable in TRPM4-deficient animals. Proteins of the same size were found in RV of a pediatric patient with tetralogy of Fallot. In untreated status, Trpm4+/+ and Trpm4−/− rats showed comparable RV contractile function and dimensions. Under pressure load (42 days after MCT injection), RV hypertrophy was significantly increased in Trpm4−/− rats compared with Trpm4+/+ controls, whereas MCT-mediated alterations in cardiac contractility and pulmonary arterial remodeling were not affected by TRPM4 inactivation in rats. Finally, TRPM4 protein expression in RV was drastically reduced in MCT-treated rats, whereas left ventricle of the same animals showed no alteration in TRPM4 expression. - Conclusions - Right ventricular pressure load evoked by MCT treatment in rats leads to a prominent downregulation of TRPM4 protein expression in the RV and complete deletion of TRPM4 expression aggravates right ventricular hypertrophy. Thus, therapeutic modulation of TRPM4 expression and activity might represent a novel approach to target right ventricular remodeling in patients with pulmonary hypertension or otherwise loaded RV. | ||
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