Abstract
The Hippo pathway plays a wide variety of roles in response to stress in the heart. Lats2, a component of the Hippo pathway, is phosphorylated by Mst1/2 and, in turn, phosphorylates YAP, causing inactivation of YAP. Lats2 stimulates apoptosis and negatively affects hypertrophy in cardiomyocytes. However, the role of Lats2 during cardiac stress is poorly understood in vivo. Lats2 is activated in the mouse heart in response to transverse aortic constriction (TAC). We used systemic Lats2 +/- mice to elucidate the role of endogenous Lats2. Cardiac hypertrophy and dysfunction induced by 4 weeks of TAC were attenuated in Lats2 +/- mice, and interstitial fibrosis and apoptosis were suppressed. Although TAC upregulated the Bcl-2 family proapoptotic (Bax and Bak) and anti-apoptotic (Bcl-2 and Bcl-xL) molecules in non-transgenic mice, TAC-induced upregulation of Bax and Bak was alleviated and that of Bcl-2 was enhanced in Lats2 +/- mice. TAC upregulated p53, but this upregulation was abolished in Lats2 +/- mice. Lats2-induced increases in apoptosis and decreases in survival in cardiomyocytes were inhibited by Pifithrin-α, a p53 inhibitor, suggesting that Lats2 stimulates apoptosis via a p53-dependent mechanism. In summary, Lats2 is activated by pressure overload, thereby promoting heart failure by stimulating p53-dependent mechanisms of cell death.
Highlights
The Hippo pathway plays a wide variety of roles in response to stress in the heart
We have shown previously that Lats[2] plays an important role in mediating apoptosis and inhibiting hypertrophy in cardiomyocytes in vitro[9]
In order to investigate the role of endogenous Lats[2], we studied the effects of a loss of Lats[2] function
Summary
The Hippo pathway plays a wide variety of roles in response to stress in the heart. Lats[2] is activated by pressure overload, thereby promoting heart failure by stimulating p53-dependent mechanisms of cell death. We have shown previously that Mst[1] is activated by cardiac stress, including ischemia/reperfusion in the heart, inducing apoptosis and suppressing autophagy in cardiomyocytes[6,7,8]. We have shown previously that Lats[2] plays an important role in mediating apoptosis and inhibiting hypertrophy in cardiomyocytes in vitro[9]. Cardiac-specific overexpression of dominant-negative Lats[2] inhibits cardiomyocyte apoptosis and enhances cardiac hypertrophy in mice in response to pressure o verload[9]. Dominant negative Lats[2] inhibits both Lats[1] and L ats[29] and protein overexpression could elicit unphysiological effects in the heart
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
