TRPM4 in radiation-induced aortic valve remodeling

Abstract

Thoracic radiation therapy may lead to unexpected cardiac remodelling, and up to 12% of patients treated with radiotherapy for breast cancer develop valvular dysfunction including regurgitation and stenosis. This phenomenon can affect both aortic and mitral valves and involve fibrosis and calcification. It is suspected that irradiation modify Ca2+ handling as well as fibroblast activity or development, but molecular determinants remain unknown. The monovalent non-selective cation channel TRPM4 is known to be involved in calcium handling since it modulates driving force for Ca2 + -entry and produced cell depolarization potentiating voltage-gated Ca2+ channels opening. It also participates in human atrial fibroblast transition to myofibroblast, a phenomenon with similarities to those observed during aortic valve stenosis. This channel exhibits a high expression in cardiac tissue and is involved in cardiac remodeling. Our aim was to evaluate the participation of TRPM4 in radiation-induced valvular damages. In order to achieve this aim we developed a model of 4 months Trpm4+/+ and Trpm4-/- mouse submitted to 10 Gy irradiation at the aortic valve. Cardiac parameters were evaluated by echography measurements at 5 months post-irradiation. At that time, mice were euthanized and hearts collected for histological assessments. In control conditions Trpm4-/- mice exhibited a left ventricular hypertrophy compared to Trpm4+/+, as previously reported in this model, but maximal velocity of aortic jet (Vmax) was similar in Trpm4+/+ and Trpm4-/- mice. Five month after irradiation, Trpm4+/+ mice developed a significant 30% increase in Vmax as well as an increase in maximal and mean pressure gradient, while no significant variation was detected in Trpm4-/- animals. Trpm4+/+ irradiated mice have shown a significant 48% increase of the surface of aortic valve leaflets compare to Trpm4+/+ control mice while no significant variation were observed in Trpm4-/- animals. These results indicate that TRPM4 promote radiation-induced valvular remodelling. Thus TRPM4 might be regarded as a target to prevent cardiac side effects in chest radiotherapy and might be involved in aortic stenosis development. This work was supported by a grant ANR-16-RHUS-0003 and conducted as part of the FHU CARNAVAL project.