CALL FOR PAPERS Comparative Genomics BDNF-mediated enhancement of inflammation and injury in the aging heart

Cai, Dongqing, Jacquelyne M. Holm, Inga J. Duignan, Jingang Zheng, Munira Xaymardan, Andrew Chin, Victoria L. T. Ballard, Jonathan N. Bella, and Jay M. Edelberg. BDNF-mediated enhancement of inflammation and injury in the aging heart. Physiol Genomics 24: 191–197, 2006. First published December 13, 2005; doi:10.1152/physiolgenomics.00165.2005.—Aging is associated with shifts in autocrine and paracrine pathways in the cardiac vasculature that may contribute to the risk of cardiovascular disease in older persons. To elucidate the molecular basis of these changes in vivo, phage-display biopanning of 3and 18-mo-old mouse hearts was performed that identified peptide epitopes with homology to brainderived neurotrophic factor (BDNF) in old but not young phage pools. Quantification of cardiac phage binding by titration and immunostaining after injection with BDNF-like phage identified a twofold increased density of the BDNF receptor, truncated Trk B, in the aging hearts. Studies focused on the receptor ligand using a rat model of transient myocardial ischemia revealed increases in cardiac BDNF associated with local mononuclear infiltrates in 24but not 4-mo-old rats. To investigate these changes, both 4and 24-mo-old rat hearts were treated with intramyocardial injections of BDNF (or PBS control), demonstrating significant inflammatory increases with activated macrophage (ED1 ) in BDNF-treated aging hearts compared with aging controls and similarly treated young hearts. Additional studies with permanent coronary occlusion following intramyocardial growth factor pretreatment revealed that BDNF significantly increased the extent of myocardial injury in older rat hearts (BDNF 35 10% vs. PBS 16.2 7.9% left ventricular injury; P 0.05) without affecting younger hearts (BDNF 15 5.1% vs. PBS 14.5 6.0% left ventricular injury). Overall, these studies suggest that age-associated changes in BDNF-Trk B pathways may predispose the aging heart to increased injury after acute myocardial infarction and potentially contribute to the enhanced severity of cardiovascular disease in older individuals.