TRPC6の薬理的な活性化は心不全を改善する

<p>A growing body of evidence suggests that transient receptor potential canonical (TRPC) 3 and 6 channels are involved in developing pathological remodeling of the heart. However, we found that activation of TRPC6 channel enhances β adrenoceptor (βAR)-stimulated myocardial positive inotropy and prevents chronic heart failure in mice by enhancing Zn²⁺ dynamics. This study aims to investigate whether TRPC6-mediated Zn²⁺ influx suppresses sympathetic overactivity-induced chronic heart failure in mice. </p><p>Chronic stimulation of βAR with isoproterenol (ISO; 30 mg/kg/day) for 4 weeks caused myocardial dysfunction in WT mice and Zn²⁺ permeation-dead (PD) TRPC6 mutant-expressing mice. Treatment with 2-[4-(2,3-dimethylphenyl)-piperazin-1-yl]-N- (2-ethoxyphenyl) acetamide (PPZ2), a TRPC3/6/7 channel activator, improved ISO-induced heart failure in WT mice but failed in TRPC6 (PD) mice. Zinpyr-1 imaging revealed that PPZ2 increased the intracellular Zn²⁺ pool in ISO-treated WT hearts, while this increase was not observed in ISO-treated TRPC6 (PD) hearts. In addition, the electrophysiological study demonstrated that TRPC6 (PD) mutant could permeate Na⁺, Ca²⁺ and K⁺ as much as WT, but failed to permeate Zn²⁺ after PPZ2 stimulation. PPZ2 improved ISO-induced impairment of L-type Ca²⁺ channel current. Furthermore, PPZ2 attenuated ISO-induced oxidative stress and supersulfide catabolism. In conclusion, these results suggest that activating TRPC6-mediated Zn²⁺ influx improves chronic heart failure by maintaining redox homeostasis.</p>