Manipulation of Cardiac Phosphatidylinositol 3-Kinase (PI3K)/Akt Signaling by Apoptosis Regulator through Modulating IAP Expression (ARIA) Regulates Cardiomyocyte Death during Doxorubicin-induced Cardiomyopathy
Manipulation of Cardiac Phosphatidylinositol 3-Kinase (PI3K)/Akt Signaling by Apoptosis Regulator through Modulating IAP Expression (ARIA) Regulates Cardiomyocyte Death during Doxorubicin-induced Cardiomyopathy
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DOI：
10.1074/jbc.m113.508143
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发表时间：
2014-01-31
影响因子：
4.8
通讯作者：
Ikeda, Koji
中科院分区：
文献类型：
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作者：
Kitamura, Youhei;Koide, Masahiro;Ikeda, Koji
背景：PI 3 K/Akt信号通路调节心肌细胞稳态的许多方面。结果：ARIA通过调节心脏PI 3 K/Akt信号通路，改善心肌细胞死亡和应激性心功能不全。结论：ARIA是一种新的参与心脏PI 3 K/Akt信号调节的因子。重要性：ARIA介导的心肌PI 3 K/Akt信号转导是治疗心功能不全的一个重要靶点，PI 3 K/Akt信号转导在心肌细胞死亡机制的调控中发挥重要作用，而心肌细胞死亡机制的改变可导致应激性心功能不全。在这里，我们报告，凋亡调节因子通过调节IAP表达（ARIA），最近发现的跨膜蛋白，调节心脏PI 3 K/Akt信号，从而修改阿霉素（DOX）诱导的心肌病的进展。相对于其他组织，ARIA在小鼠心脏中高度表达，并且它也在分离的大鼠心肌细胞中表达。ARIA在H9 c2心肌细胞中的稳定表达增加了膜相关PTEN的水平，随后降低了PI 3 K/Akt信号传导和Bad（一种促凋亡的仅BH 3蛋白）的下游磷酸化。当用DOX攻击时，ARIA表达的H9 c2细胞表现出增强的凋亡，这被siRNA介导的Bad沉默逆转。ARIA缺陷小鼠表现出正常的心脏形态和功能。然而，DOX诱导的心脏功能障碍在ARIA缺陷小鼠中显著改善，同时心肌细胞死亡和心脏纤维化减少。即使在用DOX治疗后，ARIA缺陷小鼠的心脏中Akt和Bad的磷酸化也显著增强。此外，通过心肌细胞特异性表达显性负性PI 3 K（p110）来抑制PI 3 K，可消除ARIA缺失的心脏保护作用。值得注意的是，在心肌细胞中而不是在内皮细胞中靶向激活ARIA减少了心脏PI 3 K/Akt信号传导并加剧了DOX诱导的心功能障碍。因此，这些研究揭示了ARIA操纵心脏PI 3 K/Akt信号传导的先前未描述的模式，从而将ARIA确定为预防应激诱导的心肌功能障碍的有吸引力的新靶点。
Background: The PI3K/Akt signaling regulates many aspects of cardiomyocyte homeostasis. Results: ARIA regulates cardiac PI3K/Akt signaling and modifies cardiomyocyte death and stress-induced cardiac dysfunction. Conclusion: ARIA is a novel factor involved in the regulation of cardiac PI3K/Akt signals. Significance: ARIA-mediated manipulation of cardiac PI3K/Akt signaling is an intriguing therapeutic target to treat cardiac dysfunction.PI3K/Akt signaling plays an important role in the regulation of cardiomyocyte death machinery, which can cause stress-induced cardiac dysfunction. Here, we report that apoptosis regulator through modulating IAP expression (ARIA), a recently identified transmembrane protein, regulates the cardiac PI3K/Akt signaling and thus modifies the progression of doxorubicin (DOX)-induced cardiomyopathy. ARIA is highly expressed in the mouse heart relative to other tissues, and it is also expressed in isolated rat cardiomyocytes. The stable expression of ARIA in H9c2 cardiac muscle cells increased the levels of membrane-associated PTEN and subsequently reduced the PI3K/Akt signaling and the downstream phosphorylation of Bad, a proapoptotic BH3-only protein. When challenged with DOX, ARIA-expressing H9c2 cells exhibited enhanced apoptosis, which was reversed by the siRNA-mediated silencing of Bad. ARIA-deficient mice exhibited normal heart morphology and function. However, DOX-induced cardiac dysfunction was significantly ameliorated in conjunction with reduced cardiomyocyte death and cardiac fibrosis in ARIA-deficient mice. Phosphorylation of Akt and Bad was substantially enhanced in the heart of ARIA-deficient mice even after treatment with DOX. Moreover, repressing the PI3K by cardiomyocyte-specific expression of dominant-negative PI3K (p110) abolished the cardioprotective effects of ARIA deletion. Notably, targeted activation of ARIA in cardiomyocytes but not in endothelial cells reduced the cardiac PI3K/Akt signaling and exacerbated the DOX-induced cardiac dysfunction. These studies, therefore, revealed a previously undescribed mode of manipulating cardiac PI3K/Akt signaling by ARIA, thus identifying ARIA as an attractive new target for the prevention of stress-induced myocardial dysfunction.