SIRT1 increases cardiomyocyte binucleation in the heart development.
SIRT1 increases cardiomyocyte binucleation in the heart development.
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DOI：
10.18632/oncotarget.23847
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发表时间：
2018-01-30
期刊：
影响因子：
--
通讯作者：
Zhang L
中科院分区：
文献类型：
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作者：
Shin AN;Han L;Dasgupta C;Huang L;Yang S;Zhang L
SIRT 1调节细胞衰老。我们研究了SIRT 1在发育心脏中调节心肌细胞终末分化的新作用。视黄酸（RA）诱导的H9 c2细胞双核化与SIRT 1表达增加有关。抑制SIRT 1的活性或表达显着降低RA诱导的双核。SIRT 1的表达在胎儿心脏中是最小的，在出生后第7天（P7）大鼠幼崽的心脏中显著上调。相比之下，胎儿心脏中心脏特异性miR-133 a表达较高，但在P7幼崽心脏中显着降低。miR-133 a启动子含有典型的HRE元件，缺氧可上调心脏中的miR-133 a基因表达。SIRT 1 mRNA 3′UTR具有miR-133 a结合序列，miR-133 a和缺氧抑制心肌细胞SIRT 1表达。重要的是，SIRT 1的抑制显著减少了P7幼仔心脏中的双核心肌细胞。综上所述，本研究揭示了SIRT 1的新作用及其通过miR-133 a在发育心脏的心肌细胞终末分化中的调节，并提出了一种可能影响心脏功能的潜在治疗策略。
SIRT1 regulates cell senescence. We investigated a novel role of SIRT1 in the regulation of cardiomyocyte terminal differentiation in the developing heart. Retinoic acid (RA)-induced binucleation of H9c2 cells was associated with increased SIRT1 expression. Inhibition of SIRT1 activity or expression significantly decreased RA-induced binucleation. SIRT1 expression was minimal in the fetal heart and significantly upregulated in the hearts of postnatal day 7 (P7) rat pups. In contrast, heart-specific miR-133a expression was high in the fetal heart but significantly reduced in P7 pup hearts. The miR-133a promoter contains a canonical HRE element and hypoxia upregulated miR-133a gene expression in the heart. SIRT1 mRNA 3′UTR has miR-133a binding sequences and miR-133a and hypoxia suppressed SIRT1 expression in cardiomyocytes. Of importance, inhibition of SIRT1 significantly reduced binucleated cardiomyocytes in the hearts of P7 pups. Taken together, the present study reveals a novel role of SIRT1 and its regulation by miR-133a in cardiomyocyte terminal differentiation of the developing heart, and suggests a potential therapeutic strategy that may impact cardiac function later in life.