The effect of Sav or

The effect of Sav1 or Lats1/2 inactivation on adult cardiomyocyte proliferation has also been examined. Inactivation of these Hippo pathway components in the adult heart increased cardiomyocyte DNA synthesis and karyokinesis (Heallen et al., 2013). Qualitatively, the result was similar to what was observed in Yap gain of function (Xin et al., 2013). However, inactivation of Sav1 or Lats1/2 caused quantitatively much higher levels of cardiomyocyte LY 2157299 activity (~2.5% EdU+ cardiomyocytes after 4days of labeling). This discrepancy may be due to the different experimental methods used by the two groups, or it might suggest that the Hippo pathway regulates proliferation through additional targets other than Yap. The contribution of resident cardiac progenitors in adult heart homeostasis, and their potential recruitment for therapeutic heart regeneration, has been widely debated (Kajstura et al., 2008; Bergmann et al., 2009; Senyo et al., 2013; Hsieh et al., 2007). The Hippo–Yap pathway plays a critical role in the multipotency and differentiation of embryonic stem cells, neuronal progenitors, and intestinal stem cells (Lian et al., 2010; Cao et al., 2008; Cai et al., 2010; Barry et al., 2013). These data suggest that Hippo–Yap may modulate cardiac progenitor activity. However, since most animal models used to study the cardiac function of this pathway (Table 1), they have primarily used cardiomyocyte-specific drivers that are presumed to be inactive in cardiac progenitors, experimental data on Hippo–Yap signaling in cardiac progenitors is currently lacking. Clarifying the contribution of resident cardiac progenitors to adult heart homeostasis and their potential redeployment for therapeutic heart regeneration, and the function of Hippo/Yap in this processes, are clearly priorities for future studies.
Concluding comments: harnessing Hippo/Yap for heart disease therapy The studies summarized in this review demonstrate the importance of the Hippo/Yap pathway in the regulation of heart growth during fetal development. Modulation of this pathway in the neonatal heart prolongs the neonatal regenerative window, highlighting the potential for enhancing cardiac regeneration. Yap activation in the injured adult heart is also beneficial at least in the short-term, although stimulation of cardiomyocyte proliferation was modest and additional mechanisms are also likely to contribute. Over the past two decades, many paracrine factors and their pathways have been found to stimulate cardiomyocyte proliferation, such as IGF1 (Duerr et al., 1995), perisotin (Kuhn et al., 2007), neuregulin (Baliga et al., 1999; Bersell et al., 2009), and fibroblast growth factor (Engel et al., 2005). However, these agents also cause cardiomyocyte hypertrophy (Baliga et al., 1999; McMullen et al., 2004; House et al., 2010; Oka et al., 2007), which may be deleterious to heart function in the long run. When compared with the other signaling pathways involved in cardiac repair, the Hippo/Yap pathway stands out by promoting cardiomyocyte proliferative growth and enhancing myocardial recovery after MI without stimulating cardiomyocyte hypertrophy. Why does inactivation of Yap in the late fetal heart cause progressive, lethal dilated cardiomyopathy? Does this reflect a developmental defect that becomes expressed postnatally, or an ongoing requirement for Yap in the maintenance of adult heart function? Current data from the failing adult heart suggests that Yap is required to suppress cardiomyocyte apoptosis. However, cardiomyocyte number in these failing hearts was not detectably reduced. Perhaps Yap has additional roles in the postnatal cardiomyocyte, as it does in the Drosophila eye (Jukam et al., 2013).
Acknowledgments WTP was supported by funding from the NIH (HL116461 and HL100401) and by an American Heart Association (Z.L. AHA: 12POST9580001) Established Investigator Award, and by charitable donations from Gail Federici Smith, Edward Marram, and Karen Carpenter. ZL was supported by a postdoctoral fellowship from the American Heart Association.