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  • Taken together we conclude that Lats may regulate adult card

    2018-11-08

    Taken together, we conclude that Lats may regulate adult cardiomyocyte hypertrophy independent of Yap or Tead1. Rather than controlling cardiac hypertrophic growth, the canonical Hippo/Yap pathway is crucial for regulation of cardiomyocyte survival in the adult heart. This parallels the findings in Drosophila post-mitotic neurons, where Warts and Lats but not Yki were required for the maintenance of dendrites (Emoto et al., 2006). The proteins and pathways through which Lats may regulate cardiomyocyte hypertrophic growth are currently unknown.
    Hippo/Yap in heart regeneration The finding that Hippo/Yap signaling powerfully regulates fetal heart growth and cardiomyocyte proliferation (von Gise et al., 2012; Heallen et al., 2011; Xin et al., 2011), and that Yap gain of function extends neonatal cardiomyocyte tranylcypromine Supplier activity in vivo (von Gise et al., 2012) raised the exciting possibility that this signaling pathway could be redeployed to promote adult heart regeneration and repair. Initial studies on the Hippo kinase cascade and Yap suggest that this pathway remains an important regulator of cardiomyocyte cell cycle activity in the postnatal heart, although Yap\'s potency in driving cardiomyocyte proliferation wanes with cardiomyocyte maturation. We showed that overexpression of activated Yap beginning at E8.5 dramatically stimulated cardiomyocyte proliferation (von Gise et al., 2012). In the newborn heart, Yap1 continued to drive cardiomyocyte proliferation, although the extent of cardiomyocyte proliferation was far less than the observed in early heart development (von Gise et al., 2012; Xin et al., 2013). Consistent with the stage-dependent sensitivity of cardiomyocytes to Yap-induced proliferation, overexpression of Yap under control of the βMHC promoter, which initiates a few days after E8.5, resulted in less extensive cardiac overgrowth, and these transgenic mice were viable to adulthood (Xin et al., 2011). The newborn mouse heart retains the ability to regenerate from myocardial injury, but this regenerative capacity is lost by postnatal day 7 (P7) (Porrello et al., 2011). Given the ability of Yap to promote neonatal cardiomyocyte proliferation, Xin, Olson, and colleagues tested the ability of Yap activation to prolong the regenerative window (Xin et al., 2013). P7 neonatal wild type and αMHC–aYAP transgenic mice underwent LAD ligation. Twenty-one days later, wild type mice showed extensive scar formation, loss of myocardial tissue, and ventricular dilation, while the αMHC–αYAP mice had regenerated the infarcted myocardium with minimal scar tissue. Consistent with these data, inactivating Yap negative regulators Sav1 or Lats1/2 also increased cardiomyocyte proliferation in the neonatal heart and extended the neonatal regenerative window (Heallen et al., 2013). These data suggest that neonatal inactivation of Hippo pathway kinases or activation of Yap is sufficient to maintain the proliferative competence of neonatal cardiomyocyte in a manner that enhances neonatal cardiac regeneration. Stimulating adult cardiomyocyte cell cycle re-entry has proven to be far more challenging than increasing fetal cardiomyocyte proliferation or delaying the time of neonatal cardiomyocyte cell cycle withdrawal. Thus a crucial question is whether or not Yap activation can promote adult heart regeneration and stimulate adult cardiomyocyte proliferation. When 28-day old αMHC–αYap mice or wild type controls were challenged with myocardial infarction (MI), Yap transgenic mice showed better preservation of heart function and smaller scar size at 21day post-MI (Xin et al., 2013). αMHC–αYAP mice had 2.5-fold higher cardiomyocyte proliferation compared to wild-type control post-MI. However, the extent of adult cardiomyocyte proliferation was limited — cardiomyocyte proliferation stimulated by expression of activated Yap in adult cardiomyocytes was twenty-fold lower than the rate observed in neonatal wild-type mice. These data suggest that Yap activation in the adult heart does promote cardiomyocyte proliferation, although the level of proliferation may be insufficient to support meaningful cardiac regeneration. Yap-dependent modulation of other processes, such as reduction of apoptosis (Xin et al., 2013), likely contributes to the salutary effect of Yap after MI.