Title: The role of neutrophil YAP in cardiac ischemia/reperfusion inflammation and injury
Student: Jamie Francisco, M.S.
Mentor: Dr. Dominic Del Re, PhD.
Abstract: Myocardial Infarction (MI) is the number one cause of death worldwide, claiming
more lives than the three most prevalent cancers combined. While reperfusion is currently the
gold standard treatment of ischemic injury in the heart, it paradoxically worsens cardiac
outcomes by increasing inflammation and apoptosis, furthering myocyte loss and expanding the
infarct. Despite being a major contributor to worsening cardiac outcomes, there are no available
treatments for this secondary injury caused by reperfusion, presenting a major limitation in the
treatment of MI. Neutrophils are among the first inflammatory cells recruited to the heart after
injury and their numbers have been shown to positively correlate to infarct size. Although
neutrophils contribute to acute inflammation and infarct expansion, neutrophil depletion results
in defective cardiac repair after infarct. Therefore, further investigation into the mechanisms of
specific neutrophil functions is needed to regulate inflammation and improve cardiac outcomes
during reperfusion. The long-term goal of this research is to uncover novel therapeutic targets of
proinflammatory neutrophil functions to make possible targeted modulation of inflammation
without affecting repair during reperfusion. Previous investigations by our lab and others have
identified Yes-Associated Protein (YAP), a downstream effector of the Hippo pathway, as a
critical regulator of cardiac outcomes after ischemic heart injury. Preliminary data from our
newly generated neutrophil-specific YAP KO mouse (YAP F//F: MRP8-cre) show decreased infarct
size and inflammatory gene expression when compared to controls after acute
ischemia/reperfusion (I/R). These data support our hypothesis that neutrophil YAP positively
regulates inflammation and therefore, cardiac injury, after I/R. The goal of the proposed study is
to define the role of YAP in specific pro-inflammatory neutrophil functions and the subsequent
effect on cardiac injury during reperfusion to improve cardiac outcomes after I/R injury. To
investigate this, we propose the following aims: 1) Determine cardiac injury and post infarct
inflammatory status in neutrophil-specific YAP KO mice, 2) Determine the effect of YAP
expression on neutrophil function during reperfusion and investigate the underlying mechanism.
Upon completion, we will have elucidated the role of YAP in specific neutrophil proinflammatory
functions during cardiac reperfusion. Furthermore, we believe these studies will reveal novel
therapeutic targets for the modulation of inflammation without affecting the repair mechanism in
the heart. As the injury due to reperfusion currently has no effective treatment, the results of this
work could advance the field toward improved therapeutic options for MI patients.