ABC | Volume 115, Nº2, August 2020

Review Article Serum Levels of BDNF in Cardiovascular Protection and in Response to Exercise Ivani Credidio Trombetta, 1 José Roberto DeMoura, 1,2 Cleber Rene Alves, 1 Renato Carbonari-Brito, 1 Felipe Xerez Cepeda, 1 J osé Ribeiro Lemos Jr. 2 Universidade Nove de Julho (UNINOVE), 1 São Paulo, SP - Brazil Escola de Educação Física da Polícia Militar do Estado de São Paulo, 2 São Paulo, SP – Brazil Abstract Cardiovascular disease (CVD) is currently the leading cause of death in Brazil and worldwide. In 2016, CVD accounted for more than 17 million deaths, representing 31% of all deaths globally. Molecular and genetic mechanisms may be involved in vascular protection and should be considered in new therapeutic approaches. In this sense, recent studies have reported that brain-derived neurotrophic factor (BDNF) is reduced in individuals predisposed to develop CVD, and that aerobic physical training increases the amounts of circulating BDNF. BDNF is a neurotrophin found at high concentrations in the hippocampus and cerebral cortex and is considered a key molecule for the maintenance of synaptic plasticity and survival of neuronal cells. In addition to neuronal plasticity, BDNF is also important in vascular function, promoting angiogenesis through the regulation of reactive oxygen species (ROS). However, a variant of the BDNF gene in humans, the Val66Met polymorphism (substitution of the amino acid valine for a methionine at position 66 of the codon), occurring in 20-30% of the Caucasian population, may affect plasma BDNF concentrations and its activity in all peripheral tissues containing tyrosine kinase B receptors (TrkB), such as the endothelium. Thus, we will present a discussion about the role of serum BDNF levels in cardiovascular protection, Val66Met genetic variant in vascular reactivity and the effect of physical exercise. Introduction The main causes of death from noncommunicable diseases are cardiovascular diseases (CVD). Across the world, CVD deaths increased 12.5% between 2005 and 2015, reaching 17.9 million deaths. 1 In Brazil, CVD mortality accounted for 28% of all deaths in the last five years, accounting for 38% of all deaths in the productive age range (18 to 65 years). 2 The most relevant CVD in terms of public health are heart (coronary artery disease and heart failure) and cerebrovascular diseases. Risk factors for CVD are well known (among them, obesity, dyslipidemia, diabetes and sedentary lifestyle). However, its molecular basis is complex and is linked to a wide range of biological pathways, including lipid and glucose metabolism, inflammation, vascular repair and angiogenesis. The main etiology of CVD is atherosclerosis, a complex chronic inflammatory process of the arterial wall that involves the recruitment and activation of cells in the lesion of the intima layer. This endothelial cell activation by inflammatory cytokines and oxidized lipoproteins, followed by increased adhesion of circulating blood monocytes to the endothelium and migration of vascular smooth muscle cells into the developing neointimal layer, leads to the development of the atherosclerotic plaque, progressively obstructing the vascular lumen and reducing blood flow. 3 In addition, atherosclerosis occurs in endothelial dysfunction, characterized by reduced bioavailability of nitric oxide (NO) on the wall of blood vessels. 4 Endothelial dysfunction is a marker of cardiovascular risk and is present in CVD such as hypertension, coronary artery disease and chronic heart failure. 5 Several factors have been associated with the endothelium-dependent blood flow modulation, such as the bioavailability of L-arginine, tetrahydrobiopterin (BH4), LDL-cholesterol and vascular endothelial growth factor (VEGF) levels, among others. 4 Although the brain-derived neurotrophic factor (BDNF) is directly related to the health of neurons, 6 translational and clinical experimental studies have demonstrated their strong association with the vascular system. In fact, initially neurotrophins had their actions identified basically in the development and maturation of the nervous system. However, since the late 1990s, strong evidence has emerged in the literature that neurotrophins are implicated in important cardiovascular functions. 7 More recently, an important study has demonstrated the association of circulating BDNF to the vascular system, specifically angiogenesis, through the regulation of reactive oxygen species (ROS). 8 Thus, in addition to the nervous system function, accumulated evidence suggests that BDNF is also important for the cardiovascular system. Because of the association between BDNF and angiogenesis, increased vasodilation and tissue perfusion, this neurotrophin is another important link between lifestyle and vascular health, with repercussions on brain structure and cognitive function in older adults. 9 A lifestyle that includes cognitive engagement, regular exercise, and a healthy diet is a key strategy to maintain brain health during the aging process. 9 In this context, several studies have shown that exercise is one of the main factors in increasing serum BDNF levels 10-12 Keywords Cardiovascular Diseases/mortality; BDNF; Brain-Derived Neurotrophic Factor; Endothelium Vascular; Nerve Growth Factors; Neuronal Plasticity; Polymorphism; Exercise. Mailing Address: Ivani Credidio Trombetta • Universidade Nove de Julho (UNINOVE) - Rua Vergueiro, 235/249. Postal Code 01504-001, São Paulo, SP – Brazil E-mail: ivani.trombetta@gmail.com , ivani.trombetta@uni9.pro.br Manuscript received June 07, 2019, revised manuscript February 03, 2020, accepted March 16, 2020 DOI: https://doi.org/10.36660/abc.20190368 263