Zhang Yiqiang, Matsushita Noriko, Eigler Tamar, Marbán Eduardo
Department of Medicine/Cardiology, University of Washington, USA ; Cedars-Sinai Heart Institute, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
Cedars-Sinai Heart Institute, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
J Regen Med. 2013;2:2. doi: 10.4172/2325-9620.1000108.
Mammalian heart cells undergo a marked reduction in proliferative activity shortly after birth, and thereafter grow predominantly by hypertrophy. Our understanding of the molecular mechanisms underlying cardiac maturation and senescence is based largely on studies at the whole-heart level. Here, we investigate the molecular basis of the acquired quiescence of purified neonatal and adult cardiomyocytes, and use microRNA interference as a novel strategy to promote cardiomyocyte cell cycle re-entry. Expression of cyclins and cyclin-dependent kinases (CDKs) and positive modulators were down-regulated, while CDK inhibitors and negative cell cycle modulators were up-regulated during postnatal maturation of cardiomyocytes. The expression pattern of microRNAs also changed dramatically, including increases in miR-29a, miR-30a and miR-141. Treatment of neonatal cardiomyocytes with miRNA inhibitors anti-miR-29a, anti-miR-30a, and antimiR-141 resulted in more cycling cells and enhanced expression of Cyclin A2 (CCNA2). Thus, targeted microRNA interference can reactivate postnatal cardiomyocyte proliferation.
哺乳动物心脏细胞在出生后不久增殖活性就会显著降低，此后主要通过肥大生长。我们对心脏成熟和衰老潜在分子机制的理解很大程度上基于全心脏水平的研究。在这里，我们研究纯化的新生和成年心肌细胞获得性静止的分子基础，并使用微小RNA干扰作为促进心肌细胞重新进入细胞周期的新策略。在心肌细胞出生后成熟过程中，细胞周期蛋白、细胞周期蛋白依赖性激酶（CDK）及其正向调节因子的表达下调，而CDK抑制剂和负向细胞周期调节因子上调。微小RNA的表达模式也发生了显著变化，包括miR-29a、miR-30a和miR-141的增加。用微小RNA抑制剂抗miR-29a、抗miR-30a和抗miR-141处理新生心肌细胞，导致更多的循环细胞和细胞周期蛋白A2（CCNA2）表达增强。因此，靶向微小RNA干扰可以重新激活出生后心肌细胞的增殖。
