Myocardial TRPC6 modulates stretch-induced increase in contractility via Zn<sup>2+</sup> mobilization.

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  • マウス心筋のTRPC6によるZn<sup>2+</sup>を介した伸展誘発性収縮力増加反応の制御

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<p>TRPC6 has been previously reported to be involved in cardiac mechanosensitive responses, e.g., the Anrep effect. However, its role in the Frank-Starling mechanism (FSM) remains unclear. This study investigated whether TRPC6 contributes to the stretch-induced increase in contractile force associated with the FSM. Here, we used isolated ventricular cardiomyocytes from wild-type (WT) and TRPC6−/− mice hearts. The cells were electrically stimulated at 4 Hz in normal Tyrode solution at 37 °C. Axial stretches were applied using the carbon fibre technique to generate the end-systolic force-length relation (ESFLR) curve. The slope of the ESFLR curve, an indicator of cellular contractility, was significantly steeper in TRPC6−/− mouse cardiomyocytes than in WT mouse cardiomyocytes. Transcriptome and real-time polymerase chain reaction analysis revealed that the genetic deletion of TRPC6 led to an increase in metallothionein 1 and 2, which is associated with intracellular Zn2+ concentrations ([Zn2+]i), along with an increase in ZIP8, a zinc transporter. Subsequently, zinc imaging unveiled an elevation in [Zn2+]i in TRPC6−/− mouse cardiomyocytes. Interestingly, the addition of Zn2+ to the normal Tyrode solution also prompted the contractility in WT mouse cardiomyocytes, while this augmentation was blocked by rac-3, a ZIP8 inhibitor. These results suggest that TRPC6 contributes to alterations in cardiac muscle contractility, associated with the FSM, by regulating [Zn2+]i via ZIP8.</p>

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