TRPM4 Participates in Irradiation-Induced Aortic Valve Remodeling in Mice

SIMPLE SUMMARY: Despite its benefit in cancer treatment, thoracic irradiation can induce aortic valve stenosis with fibrosis and calcification. The TRPM4 cation channel is known to participate in cellular remodeling including the transition of cardiac fibroblasts to myofibroblasts, similar to that observed during aortic valve stenosis. This study evaluates if TRPM4 is involved in irradiation-induced aortic valve damage. The aortic valve of mice was targeted by irradiation. Cardiac echography 5 months after treatment revealed an increase in aortic jet velocity, indicating stenosis. This was not observed in non-treated animals. Histological analysis revealed an increase in valvular cusp surface associated with fibrosis which was not observed in non-treated animals. The experiments were reproduced on mice after Trpm4 gene disruption. In these animals, irradiation did not induce valvular remodeling. It indicates that TRPM4 influences irradiation-induced aortic valve damage and thus could be a target to prevent such side effects of irradiation. 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.