Abstract 850: Cardiac Dysfunction in Mena Knockout Mice
Heart failure (HF) is a progressive disease associated with myriad changes in gene expression, including reversion to a fetal gene program, as well as dysregulation of cardiac β-adrenergic receptor (β-AR) signal transduction. We recently identified dramatic upregulation of a cardinal member of the Ena/VASP family, Mena, in both human and mouse heart failure. Furthermore, we found normalization of Mena expression following transgenic rescue of HF in mice or following beneficial left ventricular assist device support in humans. Mena is a cytoarchitectural protein that modulates microfilaments and interacts with cytoskeletal proteins implicated in HF. The goal of this study was to determine the functional role of Mena in the heart. We assessed cardiac function and morphology of Mena null mice by echocardiography, electrocardiography, histopathology and electron microscopy. Paradoxically, we found Mena null mice have significantly decreased basal cardiac function, prolonged PR and QRS intervals and exacerbated pathologic response to ischemia/reperfusion injury. In Mena null mice, these alterations are associated with myocyte disarray, increased interstitial fibrosis and disorganization of intercalated disks, among other myocardial ultrastructural abnormalities. Phosphorylation by cAMP-dependent protein kinase A is known to regulate Mena function. At the cellular level, we have recently found that β-AR stimulation induces phosphorylation of Mena and increases its translocation to the membrane. These data suggest a role for increased Mena expression as a compensatory response to pathological cardiac stimuli. Our data demonstrate, for the first time, the functional cardiac importance of the novel HF-associated gene Mena and its potential interaction with adrenergic signaling.