Impact of BDNF Val66Met Polymorphism on Myocardial Infarction: Exploring the Macrophage Phenotype

Abstract

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin growth factor family, well known for its role in the homeostasis of the cardiovascular system. Recently, the human BDNF Val66Met single nucleotide polymorphism has been associated with the increased propensity for arterial thrombosis related to acute myocardial infarction (AMI). Using cardiac magnetic resonance imaging and immunohistochemistry analyses, we showed that homozygous mice carrying the human BDNF Val66Met polymorphism (BDNFMet/Met) undergoing left anterior descending (LAD) coronary artery ligation display an adverse cardiac remodeling compared to wild-type (BDNFVal/Val). Interestingly, we observed a persistent presence of pro-inflammatory M1-like macrophages and a reduced accumulation of reparative-like phenotype macrophages (M2-like) in the infarcted heart of mutant mice. Further qPCR analyses showed that BDNFMet/Met peritoneal macrophages are more pro-inflammatory and have a higher migratory ability compared to BDNFVal/Val ones. Finally, macrophages differentiated from circulating monocytes isolated from BDNFMet/Met patients with coronary heart disease displayed the same pro-inflammatory characteristics of the murine ones. In conclusion, the BDNF Val66Met polymorphism predisposes to adverse cardiac remodeling after myocardial infarction in a mouse model and affects macrophage phenotype in both humans and mice. These results provide a new cellular mechanism by which this human BDNF genetic variant could influence cardiovascular disease.

Potential Relation between Plasma BDNF Levels and Human Coronary Plaque Morphology

“…On the one hand, BDNF has been reported to be increased when measured in the first hours after AMI [37], and to be associated with the severity of acute heart failure due to AMI [38]. On the other hand, reduced BDNF levels have been related to adverse cardiac remodeling after AMI [39,40]. Experimental AMI models also provided conflicting results, with some…”

“…On the one hand, BDNF has been reported to be increased when measured in the first hours after AMI [37], and to be associated with the severity of acute heart failure due to AMI [38]. On the other hand, reduced BDNF levels have been related to adverse cardiac remodeling after AMI [39,40]. Experimental AMI models also provided conflicting results, with some reports showing that BDNF reduces infarct size and ameliorates cardiac function [41], others showing that it increased the extent of inflammation and myocardial injury [42].…”

An Integrative Pharmacology-Based Strategy to Uncover the Mechanism of Xiong-Pi-Fang in Treating Coronary Heart Disease with Depression

“…5-HT metabolic disorder inhibits the cAMP signaling pathway ( Louiset et al, 2017 ). The cAMP signaling pathway was observed in both CHD and depression patients ( Amare et al, 2017 ; Wang and Mao, 2019 ; Sandrini et al, 2020 ).…”

TGFβ-Neurotrophin Interactions in Heart, Retina, and Brain

“…In macrophages BDNF promotes the shift from pro-inflammatory to reparative polarization, thereby modifying the inflammatory microenvironment [ 97 ]. It has recently been reported that a polymorphism of BDNF (Val66Met), well known to be related to mood disorders and neurodegenerative diseases, also has an impact on the reactive state of macrophages following MI, predominantly by promoting the pro-inflammatory state, thereby predisposing to adverse cardiac remodeling [ 98 , 99 ]. Thus, neurotrophins such as BDNF influence all three regenerative phases following MI.…”