Department of Physiology and Biophysics, Federal University of Minas Gerais, Av Antônio Carlos, 6627-Campus Pampulha 31270-901 Belo Horizonte, MG, Brazil.
J Mol Cell Cardiol. 2012 Oct;53(4):475-86. doi: 10.1016/j.yjmcc.2012.06.017. Epub 2012 Jul 2.
It is well established that inositol 1,4,5-trisphosphate (IP3) dependent Ca(2+) signaling plays a crucial role in cardiomyocyte hypertrophy. However, it is not yet known whether nuclear IP3 represents a Ca(2+) mobilizing pathway involved in this process. The goal of the current work was to investigate the specific role of nuclear IP3 in cardiomyocyte hypertrophic response. In this work, we used an adenovirus construct that selectively buffers IP3 in the nuclear region of neonatal cardiomyocytes. We showed for the first time that nuclear IP3 mediates endothelin-1 (ET-1) induced hypertrophy. We also found that both calcineurin (Cn)/nuclear factor of activated T Cells (NFAT) and histone deacetylase-5 (HDAC5) pathways require nuclear IP3 to mediate pathological cardiomyocyte growth. Additionally, we found that nuclear IP3 buffering inhibited insulin-like growth factor-1 (IGF-1) induced hypertrophy and prevented reexpression of fetal gene program. Together, these results demonstrated that nuclear IP3 is an essential and a conserved signal for both pathological and physiological forms of cardiomyocyte hypertrophy.
已有充分证据表明，肌醇 1,4,5-三磷酸（IP3）依赖性 Ca2+信号在心肌细胞肥大中起着至关重要的作用。然而，目前尚不清楚核 IP3 是否代表参与这一过程的钙动员途径。当前工作的目的是研究核 IP3 在心肌细胞肥大反应中的具体作用。在这项工作中，我们使用了一种腺病毒构建体，该构建体可选择性地缓冲新生心肌细胞核区域的 IP3。我们首次表明核 IP3 介导内皮素-1（ET-1）诱导的肥大。我们还发现，钙调神经磷酸酶（Cn）/激活 T 细胞的核因子（NFAT）和组蛋白去乙酰化酶-5（HDAC5）途径都需要核 IP3 来介导病理性心肌细胞生长。此外，我们发现核 IP3 缓冲抑制胰岛素样生长因子-1（IGF-1）诱导的肥大，并防止胎儿基因程序的重新表达。综上所述，这些结果表明核 IP3 是病理性和生理性心肌细胞肥大的必需且保守的信号。
