BDNF-mediated enhancement of inflammation and injury in the aging heart.
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 3- and 18-mo-old mouse hearts was performed that identified peptide epitopes with homology to brain-derived 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 24- but not 4-mo-old rats. To investigate these changes, both 4- and 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.
Cai
Dongqing
D
Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
Holm
Jacquelyne M
JM
Duignan
Inga J
IJ
Zheng
Jingang
J
Xaymardan
Munira
M
Chin
Andrew
A
Ballard
Victoria L T
VL
Bella
Jonathan N
JN
Edelberg
Jay M
JM
D000375:Aging / Q000378:metabolism*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D005260:Female; D007249:Inflammation / Q000378:metabolism*; D051379:Mice; D009203:Myocardial Infarction / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D019151:Peptide Library; D051381:Rats; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D019151:Peptide Library; D018124:Receptors, Tumor Necrosis Factor; D020797:Receptor, Platelet-Derived Growth Factor beta; D020813:Receptor, trkB