TRPM4 Participates in Irradiation-Induced Aortic Valve Remodeling in Mice

Abstract

Thoracic radiotherapy can lead to cardiac remodeling including valvular stenosis due to fibrosis and calcification. The monovalent non-selective cation channel TRPM4 is known to be involved in calcium handling and to participate in fibroblast transition to myofibroblasts, a phenomenon observed during aortic valve stenosis. The goal of this study was to evaluate if TRPM4 is involved in irradiation-induced aortic valve damage. Four-month-old Trpm4+/+ and Trpm4−/− mice received 10 Gy irradiation at the aortic valve. Cardiac parameters were evaluated by echography until 5 months post-irradiation, then hearts were collected for morphological and histological assessments. At the onset of the protocol, Trpm4+/+ and Trpm4−/− mice exhibited similar maximal aortic valve jet velocity and mean pressure gradient. Five months after irradiation, Trpm4+/+ mice exhibited a significant increase in those parameters, compared to the untreated animals while no variation was detected in Trpm4−/− mice. Morphological analysis revealed that irradiated Trpm4+/+ mice exhibited a 53% significant increase in the aortic valve cusp surface while no significant variation was observed in Trpm4−/− animals. Collagen staining revealed aortic valve fibrosis in irradiated Trpm4+/+ mice but not in irradiated Trpm4−/− animals. It indicates that TRPM4 influences irradiation-induced valvular remodeling.