Department of Cardiology and Stem Cell Program, Children's Hospital Boston, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2394-9. doi: 10.1073/pnas.1116136109. Epub 2012 Jan 30.
Heart growth is tightly controlled so that the heart reaches a predetermined size. Fetal heart growth occurs through cardiomyocyte proliferation, whereas postnatal heart growth involves primarily physiological cardiomyocyte hypertrophy. The Hippo kinase cascade is an important regulator of organ growth. A major target of this kinase cascade is YAP1, a transcriptional coactivator that is inactivated by Hippo kinase activity. Here, we used both genetic gain and loss of Yap1 function to investigate its role in regulating proliferative and physiologic hypertrophic heart growth. Fetal Yap1 inactivation caused marked, lethal myocardial hypoplasia and decreased cardiomyocyte proliferation, whereas fetal activation of YAP1 stimulated cardiomyocyte proliferation. Enhanced proliferation was particularly dramatic in trabecular cardiomyocytes that normally exit from the cell cycle. Remarkably, YAP1 activation was sufficient to stimulate proliferation of postnatal cardiomyocytes, both in culture and in the intact heart. A dominant negative peptide that blocked YAP1 binding to TEAD transcription factors inhibited YAP1 proliferative activity, indicating that this activity requires YAP1-TEAD interaction. Although Yap1 was a critical regulator of cardiomyocyte proliferation, it did not influence physiological hypertrophic growth of cardiomyocytes, because postnatal Yap1 gain or loss of function did not significantly alter cardiomyocyte size. These studies demonstrate that Yap1 is a crucial regulator of cardiomyocyte proliferation, cardiac morphogenesis, and myocardial trabeculation. Activation of Yap1 in postnatal cardiomyocytes may be a useful strategy to stimulate cardiomyocyte expansion in therapeutic myocardial regeneration.
心脏的生长受到严格的控制，以使心脏达到预定的大小。胎儿心脏的生长是通过心肌细胞增殖来实现的，而出生后的心脏生长主要涉及生理性心肌细胞肥大。Hippo 激酶级联反应是器官生长的重要调节因子。该激酶级联反应的一个主要靶标是 YAP1，它是一种转录共激活因子，其活性被 Hippo 激酶失活。在这里，我们使用 Yap1 功能的遗传获得和丧失来研究其在调节增殖性和生理性肥大性心脏生长中的作用。胎儿 Yap1 失活导致明显的致死性心肌发育不全和心肌细胞增殖减少，而胎儿 YAP1 的激活刺激心肌细胞增殖。在通常退出细胞周期的小梁心肌细胞中，增殖增强尤为显著。值得注意的是，YAP1 的激活足以刺激培养物中和完整心脏中的出生后心肌细胞的增殖。一种阻断 YAP1 与 TEAD 转录因子结合的显性负肽抑制了 YAP1 的增殖活性，表明该活性需要 YAP1-TEAD 相互作用。尽管 Yap1 是心肌细胞增殖的关键调节因子，但它不影响心肌细胞的生理性肥大生长，因为出生后 Yap1 的功能获得或丧失对心肌细胞大小没有显著影响。这些研究表明，YAP1 是心肌细胞增殖、心脏形态发生和心肌小梁化的关键调节因子。激活出生后心肌细胞中的 Yap1 可能是刺激治疗性心肌再生中心肌细胞扩张的一种有用策略。
