Ito Jumpei, Minemura Tomomi, Wälchli Sébastien, Niimi Tomoaki, Fujihara Yoshitaka, Kuroda Shun'ichi, Takimoto Koichi, Maturana Andrés D
Laboratory of Animal Cell Physiology, Graduate School of Bioagricultural Sciences, Nagoya University, Aichi 464-8601, Japan.
Translational Research Unit, Section for Cellular Therapy, Oslo University Hospital, 0379 Oslo, Norway.
Int J Mol Sci. 2021 Mar 30;22(7):3561. doi: 10.3390/ijms22073561.
Aldosterone excess is a cardiovascular risk factor. Aldosterone can directly stimulate an electrical remodeling of cardiomyocytes leading to cardiac arrhythmia and hypertrophy. L-type and T-type voltage-gated calcium (Ca) channels expression are increased by aldosterone in cardiomyocytes. To further understand the regulation of these channels expression, we studied the role of a transcriptional repressor, the inhibitor of differentiation/DNA binding protein 2 (Id2). We found that aldosterone inhibited the expression of Id2 in neonatal rat cardiomyocytes and in the heart of adult mice. When Id2 was overexpressed in cardiomyocytes, we observed a reduction in the spontaneous action potentials rate and an arrest in aldosterone-stimulated rate increase. Accordingly, Id2 siRNA knockdown increased this rate. We also observed that CaV1.2 (L-type Ca channel) or CaV3.1, and CaV3.2 (T-type Ca channels) mRNA expression levels and Ca currents were affected by Id2 presence. These observations were further corroborated in a heart specific Id2- transgenic mice. Taken together, our results suggest that Id2 functions as a transcriptional repressor for L- and T-type Ca channels, particularly CaV3.1, in cardiomyocytes and its expression is controlled by aldosterone. We propose that Id2 might contributes to a protective mechanism in cardiomyocytes preventing the presence of channels associated with a pathological state.
醛固酮过量是一种心血管危险因素。醛固酮可直接刺激心肌细胞发生电重构，导致心律失常和心肌肥大。醛固酮可使心肌细胞中L型和T型电压门控钙（Ca）通道的表达增加。为了进一步了解这些通道表达的调控机制，我们研究了一种转录抑制因子——分化抑制/DNA结合蛋白2（Id2）的作用。我们发现醛固酮可抑制新生大鼠心肌细胞和成年小鼠心脏中Id2的表达。当在心肌细胞中过表达Id2时，我们观察到自发动作电位频率降低，醛固酮刺激的频率增加受到抑制。相应地，Id2的小干扰RNA敲低则增加了该频率。我们还观察到，Id2的存在会影响CaV1.2（L型钙通道）或CaV3.1和CaV3.2（T型钙通道）的mRNA表达水平及钙电流。在心脏特异性Id2转基因小鼠中，这些观察结果得到了进一步证实。综上所述，我们的结果表明，Id2在心肌细胞中作为L型和T型钙通道，尤其是CaV3.1的转录抑制因子发挥作用，其表达受醛固酮调控。我们提出，Id2可能有助于心肌细胞中的一种保护机制，防止与病理状态相关的通道出现。
