ABC | Volume 115, Nº2, August 2020

Review Article Trombetta et al. BDNF in cardiovascular protection and exercise Arq Bras Cardiol. 2020; 115(2):263-269 and that increasing BDNF levels is the key element that links exercise to cognitive benefits. 13 However, variations in the levels of circulating BDNF, including its increase in response to physical training, 12 can be explained by a genetic variant of BDNF, a functional single-nucleotide polymorphism (SNP), responsible for the substitution of the amino acid Valine to Methionine at position 66 of the codon. The Val66Met polymorphism, a condition that occurs in 20-30% of the Caucasian population, 14-16 impairs both regulated secretion and intracellular traffic of BDNF. 14,17 These new findings have opened a new field of research in cardiovascular and therapeutic medicine. Brain-Derived Neurotrophic Factor (BDNF) BDNF is the most expressed neurotrophin in the central nervous system, found at high concentrations in the hippocampus and cerebral cortex. It is a key molecule involved in the maintenance of synaptic plasticity and synaptogenesis of the hippocampus, a site of memory acquisition and consolidation. 18,19 The altered production and secretion of BDNF have been demonstrated in several neurodegenerative disorders , such as Alzheimer’s and Parkinson’s disease. 20-22 In cognitively normal individuals, the concentration of BDNF in the cerebrospinal fluid decreases throughout life in the absence of dementia, and a lower concentration of BDNF in the cerebrospinal fluid was strongly associated with impaired memory and lower executive function. 23 Current knowledge points to the fact that abnormal cognition is associated with BDNF decrease in the hippocampus, which is a determining factor in the impairment of factors such as learning skills, depression, mood, anxiety disorders and schizophrenia. 24 While BDNF promotes neuronal survival and enhances synaptic plasticity by activating its tyrosine kinase receptor B (TrkB), its precursor, proBDNF, acts antagonistically, resulting in cell apoptosis when interacting with the p75 receptor of neurotrophins (p75NTR). This important function demonstrates that both are involved in different physiological functions. 25,26 The BDNF is produced presynaptically in the cell bodies of the sensory neurons projected in the dorsal horn, whereas in the hippocampus it is produced predominantly by the postsynaptic dendrites. 22,27,28 Peripherally, serum BDNF is found in blood plasma platelets and consists of vascular endothelial cells and peripheral mononuclear blood cells. 29,30 Its therapeutic potential is characterized by its ability to freely cross the blood-brain barrier in both directions via high saturation capacity of the carrier system. 22,30,31 In the peripheral nervous system, BDNF still plays an additional role, acting on axonal regeneration. It is worth mentioning that the BDNF gene and its TrkB receptor are expressed not only in the brain, but also in other parts of the body, such as the heart, lungs and endothelial tissue, 26,32,33 demonstrating its function in other organs and tissues of the body. The BDNF gene is located on the short arm (p) of chromosome 11 (11p13) and comprises 11 exons and 9 functional promoters. 34 A naturally-occurring functional polymorphism in the human BDNF gene at nucleotide 196 (G/A) encodes a substitution of amino acid valine to methionine at position 66 (Val66Met or Met66Met), which besides resulting in lower production and circulating amounts of BDNF, 14 has been associated with greater susceptibility to neurodegenerative disorders. Functionally, the Met66Met and Val66Met polymorphisms cause impairments in the intracellular traffic and in regulated secretion in neurons. 14,17 In fact, the inheritance of this polymorphism has been associated with poor cognitive performance in healthy elderly individuals 35 and memory impairment of individuals. 14 Additionally, the Val66Met polymorphism leads to 4 to 11% lower hippocampal volume observed by magnetic resonance imaging in healthy adults. 23 BNDF and Cardiovascular Function The link between heart disease and cognitive impairment has been reported in the literature. 36,37 Some authors believe that the mechanism of “cardiogenic dementia” involves chronic cerebral hypoperfusion caused by the reduction in cardiac output due to various cardiovascular diseases. 38,39 Although the association between cognitive disorders and cardiovascular risk factors is a complex one and possibly mediated by different mechanisms, the presence of clinically manifest or silent cerebral microvascular changes are involved. In addition, a recent study 24 provided new insights into the potential molecular mechanism by which heart disease induces brain dysfunction. These authors, studying a transgenic mouse model that has specific microRNA-1-2 (miR-1-2) cardiac overexpression, have observed that cardiac overexpression of miR-1 also induced behavioral abnormalities that are associated with the negative regulation of BDNF expression in the hippocampus. A broader understanding of how heart disease affects cognitive function may lead to new therapeutic strategies. The importance of circulating levels of BDNF in cardiovascular protection was evident in the prospective cohort study of the Framingham Heart Study (FHS). 40 To evaluate a potentially causal association between the levels of BDNF and CVD, a Mendelian randomization analysis was performed using the goals of the CARDIoGRAM (Coronary Artery Disease Genome-Wide Replication and Meta-Analysis) study. In this study, conducted with a large community-based sample, the researchers observed that higher levels of BDNF are associated with a lower risk of cardiovascular events and death, regardless of the standard risk factors, including low- grade inflammation markers, body mass index (BMI), physical activity and depression. 40 In fact, an important role of BDNF in the cardiovascular system is the promotion of vascular angiogenesis and increase in capillary density. 41 Studies have shown that BDNF acts on endothelial cells promoting neovascularization in response to hypoxic stimuli via the Akt pathway. 42-44 The first evidence of BDNF involvement in the angiogenesis process came from the study by Donovan et al. 45 about the development of the embryonic myocardium, in which it was shown that the overexpression of BDNF is associated with an increase in capillary density. Recently, an elegant experimental study demonstrated for the first time that BDNF promotes the formation of angiogenic tubes through the generation of ROS 264