Loss of cardiomyocytes in response to acute myocardial infarction (MI) contributes significantly to the development of chronic heart failure, a major source of morbidity and mortality in the US. Current therapies used to treat acute MI are insufficient and contribute to heart damage by promoting reperfusion injury, which exacerbates cardiomyocyte death following ischemia. Therefore, a more comprehensive understanding of the mechanisms of reperfusion injury may generate novel therapeutic strategies to meet this clinical need. Our previous work demonstrated a critical role for the pro-apoptotic kinase and core component of the Hippo signaling pathway, Mst1, in mediating injury following ischemia/reperfusion (I/R) and MI, yet its regulation remains unclear. As shown in this proposal, we have demonstrated that the tumor suppressor Neurofibromin 2 (NF2) is activated in the myocardium during reperfusion, that NF2 modulates Mst1 activation in cardiomyocytes, and that depletion of NF2 expression specifically in cardiomyocytes affords protection from global I/R injury in perfused ex vivo mouse hearts. Moreover, our preliminary results also suggest that a subpopulation of Mst1 translocates to the nucleus and interacts with nuclear NF2 during oxidative stress. Therefore, we propose that NF2 promotes cardiomyocyte apoptosis and I/R injury through activation of nuclear Mst1. This study will provide new insight into an emerging and fundamentally important signaling pathway in the heart, and elucidate the functional significance of this signaling mechanism as it pertains to the clinically relevant model of I/R injury. Results from this project could allow for the development of strategies to better treat MI patients.
Our Specific Aims are:
Aim 1 : To test the hypothesis that endogenous NF2 and subsequent canonical Hippo signaling are critical mediators of myocardial ischemia/reperfusion injury and heart failure.
Aim 2 : To test the hypothesis that MYPT-1/NF2/Mst1/Lats2 forms a complex in the cardiomyocyte nucleus to regulate canonical Hippo signaling.
The resulting injury suffered by patients with acute myocardial infarction often progresses to heart failure making it an epidemic problem in the United States. Current treatments are insufficient; therefore this project will further clarify the mechanisms responsible for heart injury and failure. This project has the potential to identify new therapeutic targets for patients with myocardial infarction.
