Use of Multifactorial Treatments to Address the Challenge of Translating Experimental Myocardial Infarct Reduction Strategies.

Myocardial tissue damage that occurs during an ischemic event leads to a spiraling deterioration of cardiac muscle structural and functional integrity. Reperfusion is the only known efficacious strategy and is the most commonly used treatment to reduce injury and prevent remodeling. However, timing is critical, and the procedure is not always feasible for a variety of reasons. The complex molecular basis for cardioprotection has been studied for decades but formulation of a viable therapeutic that can significantly attenuate myocardial injury remains elusive. In this review, we address barriers to the development of a fruitful approach that will substantially improve the prognosis of those suffering from this widespread and largely unmitigated disease. Furthermore, we proffer that ephrinA1, a candidate molecule that satisfies many of the important criteria discussed, possesses robust potential to overcome these hurdles and thus offers protection that surpasses the limitations currently observed.

EphrinA1-Fc attenuates myocardial ischemia/reperfusion injury in mice.

EphrinA1, a membrane-bound receptor tyrosine kinase ligand expressed in healthy cardiomyocytes, is lost in injured cells following myocardial infarction. Previously, we have reported that a single intramyocardial injection of chimeric ephrinA1-Fc at the time of ischemia reduced injury in the nonreperfused myocardium by 50% at 4 days post-MI by reducing apoptosis and inflammatory cell infiltration. In a clinically relevant model of acute ischemia (30min)/reperfusion (24hr or 4 days) injury, we now demonstrate that ephrinA1-Fc reduces infarct size by 46% and completely preserves cardiac function (ejection fraction, fractional shortening, and chamber dimensions) in the short-term (24hrs post-MI) as well as long-term (4 days). At 24 hours post-MI, diminished serum inflammatory cell chemoattractants in ephrinA1-Fc-treated mice reduces recruitment of neutrophils and leukocytes into the myocardium. Differences in relative expression levels of EphA-Rs are described in the context of their putative role in mediating cardioprotection. Validation by Western blotting of selected targets from mass spectrometry analyses of pooled samples of left ventricular tissue homogenates from mice that underwent 30min ischemia and 24hr of reperfusion (I/R) indicates that ephrinA1-Fc administration alters several regulators of signaling pathways that attenuate apoptosis, promote autophagy, and shift from FA metabolism in favor of increased glycolysis to optimize anaerobic ATP production. Taken together, reduced injury is due a combination of adaptive metabolic reprogramming, improved cell survival, and decreased inflammatory cell recruitment, suggesting that ephrinA1-Fc enhances the capacity of the heart to withstand an ischemic insult.

Ephrin-A1-mediated dopaminergic neurogenesis and angiogenesis in a rat model of Parkinson's disease.

Cells of the neural stem cell lineage in the adult subventricular zone (SVZ) respond to brain insult by increasing their numbers and migrating through the rostral migratory stream. However, in most areas of the brain other than the SVZ and the subgranular zone of the dentate gyrus, such a regenerative response is extremely weak. Even these two neurogenic regions do not show extensive regenerative responses to repair tissue damage, suggesting the presence of an intrinsic inhibitory microenvironment (niche) for stem cells. In the present study, we assessed the effects of injection of clustered ephrin-A1-Fc into the lateral ventricle of rats with unilateral nigrostriatal dopamine depletion. Ephrin-A1-Fc clustered by anti-IgG(Fc) antibody was injected stereotaxically into the ipsilateral lateral ventricle of rats with unilateral nigrostriatal lesions induced by 6-hydroxydopamine, and histologic analysis and behavioral tests were performed. Clustered ephrin-A1-Fc transformed the subventricular niche, increasing bromodeoxyuridine-positive cells in the subventricular area, and the cells then migrated to the striatum and differentiated to dopaminergic neurons and astrocytes. In addition, clustered ephrin-A1-Fc enhanced angiogenesis in the striatum on the injected side. Along with histologic improvements, behavioral derangement improved dramatically. These findings indicate that the subventricular niche possesses a mechanism for regulating both stem cell and angiogenic responses via an EphA-mediated signal. We conclude that activation of EphA receptor-mediated signaling by clustered ephrin-A1-Fc from within the lateral ventricle could potentially be utilized in the treatment of neurodegenerative diseases such as Parkinson's disease.