Aims

After summarizing current concepts for the role of TRPC cation channels in cardiac cells and in processes triggered by mechanical stimuli arising e.g. during pressure overload, we analysed the role of TRPC1 and TRPC4 for background Ca²⁺ entry (BGCE) and for cardiac pressure overload induced transcriptional remodelling.

Methods and results

Mn²⁺-quench analysis in cardiomyocytes from several Trpc-deficient mice revealed that both TRPC1 and TRPC4 are required for BGCE. Electrically-evoked cell shortening of cardiomyocytes from TRPC1/C4-DKO mice was reduced, whereas parameters of cardiac contractility and relaxation assessed in vivo were unaltered. As pathological cardiac remodelling in mice depends on their genetic background, and the development of cardiac remodelling was found to be reduced in TRPC1/C4-DKO mice on a mixed genetic background, we studied TRPC1/C4-DKO mice on a C57BL6/N genetic background. Cardiac hypertrophy was reduced in those mice after chronic isoproterenol infusion (−51.4%) or after one week of transverse aortic constriction (TAC; −73.0%). This last manoeuvre was preceded by changes in the pressure overload induced transcriptional program as analysed by RNA sequencing. Genes encoding specific collagens, the Mef2 target myomaxin and the gene encoding the mechanosensitive channel Piezo2 were up-regulated after TAC in wild type but not in TRPC1/C4-DKO hearts.

Conclusions

Deletion of the TRPC1 and TRPC4 channel proteins protects against development of pathological cardiac hypertrophy independently of the genetic background. To determine if the TRPC1/C4-dependent changes in the pressure overload induced alterations in the transcriptional program causally contribute to cardio-protection needs to be elaborated in future studies.

中文翻译：

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压力超负荷诱导心脏重塑后由 TRPC1/C4 介导的背景 Ca2+ 进入调节的转录特征。

宗旨

在总结了 TRPC 阳离子通道在心脏细胞中的作用以及由机械刺激引发的过程（例如在压力超负荷期间）的当前概念之后，我们分析了 TRPC1 和 TRPC4 对背景 Ca ²⁺进入（BGCE）和心脏压力超负荷诱导的作用转录重构。

方法和结果

来自几个Trpc 缺陷小鼠的心肌细胞中的Mn ^{2+ -}猝灭分析表明，BGCE 需要 TRPC1 和 TRPC4。来自 TRPC1/C4-DKO 小鼠的心肌细胞的电诱发细胞缩短减少，而在体内评估的心脏收缩力和舒张参数没有改变。由于小鼠的病理性心脏重塑取决于其遗传背景，并且发现混合遗传背景下的 TRPC1/C4-DKO 小鼠心脏重塑的发展减少，我们研究了 C57BL6/N 遗传背景下的 TRPC1/C4-DKO 小鼠背景。在慢性输注异丙肾上腺素 (-51.4%) 或横向主动脉缩窄 1 周后 (TAC; -73.0%)，这些小鼠的心脏肥大减少。正如通过 RNA 测序分析的那样，在最后一次操作之前，压力超载诱导的转录程序发生了变化。编码特定胶原蛋白的基因、Mef2 目标肌细胞蛋白和编码机械敏感通道Piezo2的基因在 TAC 后在野生型中上调，但在 TRPC1/C4-DKO 心脏中没有上调。

结论

删除 TRPC1 和 TRPC4 通道蛋白可防止病理性心脏肥大的发展，与遗传背景无关。为了确定 TRPC1/C4 依赖的压力过载引起的转录程序改变的变化是否对心脏保护有因果关系，需要在未来的研究中详细说明。