Heart failure (HF) is associated with myriad changes in cardiac gene expression. We recently found expression of Mena to be a novel predictor of HF. Furthermore, Mena expression is normalized following a genetic rescue of HF in mice, and following beneficial left ventricular assist device support in humans. Mena can alter microfilament dynamics and interacts with cytoskeletal proteins implicated in HF. Its appropriate expression and localization are required for normal axon migration, and its expression has been associated with breast cancer. Normal cardiac Mena expression is progressively decreased from neonate to low levels in the adult. Our preliminary data indicate Mena-/- mice develop progressive cardiac dysfunction, fibrosis, conduction abnormality, and exacerbated pathologic response to cardiac injury. We hypothesize increased Mena expression is protective in HF and may be an important compensatory response to cardiac stress ultimately superceded by other factors. Regulation of Mena function occurs via phosphorylation by cAMP-dependent protein kinase A (PKA). In response to acute 2-AR stimulation, Mena is phosphorylated by cAMP-dependent protein kinase A (PKA), shows increased membrane localization and interaction with Ezrin, actin and other proteins known to regulate both 2-AR signaling and cytoskeletal dynamics. Collectively, our data suggest Mena plays an important role in the heart. To test the hypothesis that regulation of Mena expression, activity and interaction with Ezrin plays an important role in cardiac and 2-AR function under basal and pathophysiologic conditions, we propose the following three specific aims.
Each aim utilizes genetically engineered mouse models, in vitro studies, isolated cardiomyocyte contractility, and in vivo characterization. 1. Determine the role of Mena in the heart at baseline and in response to pathologic cardiac stimuli. 2. Determine the role of Mena phosphorylation in modulating cardiac function and 2-AR signaling. 3. Determine the nature and role of Mena-Ezrin interactions in cardiomyocyte function and 2-AR signaling. RELEVENCE: This proposal addresses fundamental cardiovascular biology regarding the cardiac role of Mena and its potential interactions with and regulation by 2-ARs.Heart failure is a debilitating disease with poor prognosis. This proposal aims to determine the functional role of the newly identified HF-associated gene named Mena, potentially providing novel diagnostic/therapeutic targets. ? ? ?
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