NF2 Activates Hippo Signaling and Promotes Ischemia/Reperfusion Injury in Heart

抄録

Background

Ischemic heart disease is a major component of cardiovascular disease and a leading cause of death worldwide. Although much progress has been made in understanding the causes of ischemic heart disease, the molecular underpinnings that occur during ischemia/reperfusion (I/R) injury have not yet been fully elucidated.

Neurofibromin 2 (NF2) is an established tumor suppressor that promotes apoptosis and inhibits growth in a variety of cell types, yet its function in cardiomyocytes remains largely unknown. Studies in Drosophila have provided evidence that NF2 can regulate the activity of Hippo signaling, thereby modulating cell proliferation and survival. Yet, to date, evidence linking NF2 and Hippo signaling, in mammalian systems is limited. Therefore we examined whether NF2 modulates Mammalian sterile 20-like kinase 1 (Mst1)/ Yes-associated protein (YAP) signaling known as Hippo signaling in the mammalian heart to promote acute myocardial injury.

Methods and Results

We investigated the function of NF2 in isolated cardiomyocytes and mouse myocardium at baseline and in response to oxidative stress. NF2 was activated in cardiomyocytes subjected to H2O2 and in murine hearts subjected to I/R. Increased NF2 expression promoted the activation of Mst1 and the inhibition of Yap, whereas knockdown of NF2 attenuated these responses following oxidative stress. NF2 increased apoptosis of cardiomyocytes that appeared dependent on Mst1 activity. Mice deficient for NF2 in cardiomyocytes, NF2 cardiac-specific knockout (CKO), were protected against global I/R ex vivo and showed improved cardiac functional recovery. Moreover, NF2 CKO mice were protected against I/R injury in vivo and showed upregulation of Yap target gene expression. Mechanistically, we observed nuclear association between NF2 and its activator myosin phosphatase targeting subunit (MYPT)-1 in cardiomyocytes, and a subpopulation of stress-induced nuclear Mst1 was diminished in NF2 CKO hearts. Finally, mice deficient for both NF2 and Yap failed to show protection against I/R indicating that Yap is an important target of NF2 in the adult heart.

Conclusions

NF2 is activated by oxidative stress in cardiomyocytes and mouse myocardium and facilitates apoptosis. NF2 promotes I/R injury through activation of Mst1 and inhibition of Yap, thereby regulating Hippo signaling in the adult heart.