BDNF-mediated enhancement of inflammation and injury in the aging heart

Abstract

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.

Brain derived neurotrophic factor (BDNF) in cardiometabolic physiology and diseases

“…Since administration of BDNF resulted in an increase in the myocardial injury and damage after artificial occlusion in the aging animal heart and this was linked to macrophage-derived inflammation (14), the action of BDNF might be thought deleterious in this case; however, it is also possible that BDNF upregulation can be a local and/or systemic response to injury, controlled by the nervous system. Because, in the ischemic myocardium, BDNF can improve angiogenesis and left ventricular function (21).…”

“…Current research indicates that BDNF participates in the pathogenesis of many immune, inflammatory or metabolic events inside and outside the nervous system. Like other neurotrophins, BDNF and/or its receptor are synthesized in many non-neuronal tissues and cell types including developing heart (12), atherosclerotic vessels (13), macrophages (14), endothelial cells (12) and vascular smooth muscle cells (13), which could explain why this peptide is thought to be involved in the mechanism of atherosclerotic diseases.…”

Effect of Brain Derived Neurotrophic Factor, In Relation to Diet and Lifestyle Factors, for Prevention of Neuropsychiatric and Vascular Diseases and Diabetes

“…There is evidence that BDNF is also involved in all the inflammatory diseases; myocardial injury, rheumatological conditions, inflammatory bowel disease and atopic dermatitis, apart from insulin resistance, obesity, type 2 diabetes and metabolic syndrome [60][61][62][63][64]. BDNF deficiency observed in association with these diseases indicates that it may inhibit inflammation and inflammation can neutralize same causing a decrease in BDNF levels.…”

Homo obesus: A Metabotrophin-Deficient Species. Pharmacology and Nutrition Insight

“…Adiponectin [5,9,10,28,42] NGF [2][3][4][5][6][7]12,18] BDNF [2,[18][19][20][21]41,[47][48][49] Angiopoietin-like protein 4 [13], IL-10, IL-1 receptor antagonist* Ciliary neurotrophic factor* Glial cell line-derived neurotrophic factor* Bone morphogenetic protein-9* Leukemia inhibitory factor* Metallothionein-I, -II* Incretins (glucagon-like protein-1, glucose-dependent insulinotropic protein) [26,27] …”