Executioner Caspase-3 and 7 Deficiency Reduces Myocyte Number in the Developing Mouse Heart.
Executioner Caspase-3 and 7 Deficiency Reduces Myocyte Number in the Developing Mouse Heart.
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DOI：
10.1371/journal.pone.0131411
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Sanchis D
中科院分区：
文献类型：
--
作者：
Cardona M;López JA;Serafín A;Rongvaux A;Inserte J;García-Dorado D;Flavell R;Llovera M;Cañas X;Vázquez J;Sanchis D
执行者半胱天冬酶-3和-7是促进细胞死亡的蛋白酶，但正在发现非凋亡作用。心脏仅在发育过程中表达半胱天冬酶，这表明它们有助于器官成熟过程。因此，我们的目的是确定新的功能，半胱天冬酶在心脏发育。我们在小鼠心肌中诱导了执行者caspase-3和-7的同时缺失，并研究了其影响。半胱天冬酶敲除的心脏在出生时发育不良，通过肌细胞肥大逐渐达到正常重量。为了确定参与这些影响的分子途径，我们使用基于微阵列的转录组学和多重定量蛋白质组学来比较不同发育阶段的野生型和刽子手半胱氨酸天冬氨酸蛋白酶缺陷心肌。转录组学显示，在新生儿半胱天冬酶缺乏的心脏中，促进DNA复制和细胞周期进程的基因表达减少，这表明肌细胞增殖减少，并且在成人无效心肌中，结构蛋白的非心脏亚型表达减少。蛋白质组学显示参与氧化磷酸化的蛋白质丰度减少，伴随着糖酵解酶丰度增加，这强调了半胱天冬酶缺失心肌的代谢成熟延迟。相关基因的mRNA表达和蛋白质丰度之间的相关性得到了证实，但转录组学和蛋白质组学确定了发育中心脏中受半胱天冬酶影响的互补分子途径。在培养的心肌细胞中强制表达野生型或无蛋白水解活性的半胱天冬酶诱导促进细胞分裂的基因表达。结果表明，执行caspase可以调节心脏的细胞和成熟过程中的发展，提供了新的信息caspase生物学和心脏发育。
Executioner caspase-3 and -7 are proteases promoting cell death but non-apoptotic roles are being discovered. The heart expresses caspases only during development, suggesting they contribute to the organ maturation process. Therefore, we aimed at identifying novel functions of caspases in heart development. We induced simultaneous deletion of executioner caspase-3 and -7 in the mouse myocardium and studied its effects. Caspase knockout hearts are hypoplastic at birth, reaching normal weight progressively through myocyte hypertrophy. To identify the molecular pathways involved in these effects, we used microarray-based transcriptomics and multiplexed quantitative proteomics to compare wild type and executioner caspase-deficient myocardium at different developmental stages. Transcriptomics showed reduced expression of genes promoting DNA replication and cell cycle progression in the neonatal caspase-deficient heart suggesting reduced myocyte proliferation, and expression of non-cardiac isoforms of structural proteins in the adult null myocardium. Proteomics showed reduced abundance of proteins involved in oxidative phosphorylation accompanied by increased abundance of glycolytic enzymes underscoring retarded metabolic maturation of the caspase-null myocardium. Correlation between mRNA expression and protein abundance of relevant genes was confirmed, but transcriptomics and proteomics indentified complementary molecular pathways influenced by caspases in the developing heart. Forced expression of wild type or proteolytically inactive caspases in cultured cardiomyocytes induced expression of genes promoting cell division. The results reveal that executioner caspases can modulate heart’s cellularity and maturation during development, contributing novel information about caspase biology and heart development.
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影响因子：
8.8
作者：
Dillon CP;Oberst A;Weinlich R;Janke LJ;Kang TB;Ben-Moshe T;Mak TW;Wallach D;Green DR
通讯作者：
Green DR
影响因子：
64.5
作者：
Field, SJ;Tsai, FY;Greenberg, ME
通讯作者：
Greenberg, ME
MST1通过磷酸化和抑制BCL-XL促进心肌细胞凋亡。
影响因子：
16
作者：
Del Re, Dominic P.;Matsuda, Takahisa;Zhai, Peiyong;Maejima, Yasuhiro;Jain, Mohit Raja;Liu, Tong;Li, Hong;Hsu, Chiao-Po;Sadoshima, Junichi
通讯作者：
Sadoshima, Junichi
影响因子：
10.8
作者：
Ebelt, Henning;Zhang, Ying;Braun, Thomas
通讯作者：
Braun, Thomas
影响因子：
4
作者：
Brentnall, Matthew;Weir, David B.;Boise, Lawrence H.
通讯作者：
Boise, Lawrence H.