The Emerging Role of BDNF/TrkB Signaling in Cardiovascular Diseases

Zhang

et al. 2021

Front. Aging Neurosci.

Vitamin A deficiency (VAD) plays an essential role in the pathogenesis of Alzheimer’s disease (AD). However, the specific mechanism by which VAD aggravates cognitive impairment is still unknown. At the intersection of microbiology and neuroscience, the gut-brain axis is undoubtedly contributing to the formation and function of neurological systems, but most of the previous studies have ignored the influence of gut microbiota on the cognitive function in VAD. Therefore, we assessed the effect of VAD on AD pathology and the decline of cognitive function in AD model mice and determined the role played by the intestinal microbiota in the process. Twenty 8-week-old male C57BL/6J amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice were randomly assigned to either a vitamin A normal (VAN) or VAD diet for 45 weeks. Our results show that VAD aggravated the behavioral learning and memory deficits, reduced the retinol concentration in the liver and the serum, decreased the transcription of vitamin A (VA)-related receptors and VA-related enzymes in the cortex, increased amyloid-β peptides (Aβ40 and Aβ42) in the brain and gut, upregulate the translation of beta-site APP-cleaving enzyme 1 (BACE1) and phosphorylated Tau in the cortex, and downregulate the expression of brain-derived neurotrophic factor (BDNF) and γ-aminobutyric acid (GABA) receptors in the cortex. In addition, VAD altered the composition and functionality of the fecal microbiota as exemplified by a decreased abundance of Lactobacillus and significantly different α- and β-diversity. Of note, the functional metagenomic prediction (PICRUSt analysis) indicated that GABAergic synapse and retinol metabolism decreased remarkably after VAD intervention, which was in line with the decreased expression of GABA receptors and the decreased liver and serum retinol. In summary, the present study provided valuable facts that VAD exacerbated the morphological, histopathological, molecular biological, microbiological, and behavioral impairment in the APP/PS1 transgenic mice, and the intestinal microbiota may play a key mediator role in this mechanism.

Section: Discussionmentioning

confidence: 99%

Vitamin A Deficiency Exacerbates Gut Microbiota Dysbiosis and Cognitive Deficits in Amyloid Precursor Protein/Presenilin 1 Transgenic Mice

Zhang

et al. 2021

Front. Aging Neurosci.

“…BDNF had a negative correlation with a myocardial damage marker. A recent review highlighted that BDNF acts on myocardial tissue by decreasing the cardiomyocyte apoptosis and mitochondrial dysfunction and increasing angiogenesis, cardiomyocyte contraction, and calcium cycling via tropomyosin-related kinase receptor B (TrkB) signaling pathways (Hang et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Time Course and Role of Exercise-Induced Cytokines in Muscle Damage and Repair After a Marathon Race

et al. 2021

Endurance exercise induces an increase in the expression of exercise-induced peptides that participate in the repair and regeneration of skeletal muscles. The present study aimed to evaluate the time course and role of exercise-induced cytokines in muscle damage and repair after a marathon race. Fifty-seven Brazilian male amateur marathon finishers, aged 30–55 years, participated in this study. The blood samples were collected 24 h before, immediately after, and 24 and 72 h after the São Paulo International Marathon. The leukogram and muscle damage markers were analyzed using routine automated methodology in the clinical laboratory. The plasma levels of the exercise-induced cytokines were determined using the Human Magnetic Bead Panel or enzyme-linked immunosorbent assays [decorin and growth differentiation factor 15 (GDF-15)]. A muscle damage was characterized by an increase in plasma myocellular proteins and immune changes (leukocytosis and neutrophilia). Running the marathon increased interleukin (IL)-6 (4-fold), IL-8 (1.5-fold), monocyte chemoattractant protein-1 (2.4-fold), tumor necrosis factor alpha (TNF-α) (1.5-fold), IL-10 (11-fold), decorin (1.9-fold), GDF-15 (1.8-fold), brain-derived neurotrophic factor (BDNF) (2.7-fold), follistatin (2-fold), and fibroblast growth factor (FGF-21) (3.4-fold) plasma levels. We also observed a reduction in musclin, myostatin, IL-15, and apelin levels immediately after the race (by 22–36%), 24 h (by 26–52%), and 72 h after the race (by 25–53%). The changes in BDNF levels were negatively correlated with the variations in troponin levels (r = −0.36). The variations in IL-6 concentrations were correlated with the changes in follistatin (r = 0.33) and FGF-21 (r = 0.31) levels after the race and with myostatin and irisin levels 72 h after the race. The changes in IL-8 and IL-10 levels had positive correlation with variation in musclin (p < 0.05). Regeneration of exercise-induced muscle damage involves the participation of classical inflammatory mediators, as well as GDF-15, BDNF, follistatin, decorin, and FGF-21, whose functions include myogenesis, mytophagia, satellite cell activation, and downregulation of protein degradation. The skeletal muscle damage markers were not associated to myokines response. However, BDNF had a negative correlation with a myocardial damage marker. The classical anti-inflammatory mediators (IL-10, IL-8, and IL-6) induced by exercise are associated to myokines response immediately after the race and in the recovery period and may affect the dynamics of muscle tissue repair.

“…At the time of hypoxia for 3 h, Cav3.1 -mRNA and Cav3.2 -mRNA were increased by 166% and 67%, respectively. Although BDNF is highly expressed in the brain, growing evidence indicates that BDNF is also expressed in the heart and is involved in cardiac pathophysiology [ 15 , 16 ]. We then examined the possible involvement of BDNF and its high affinity receptor tropomyosin-related kinase B (TrkB) in the hypoxic conditions of cardiomyocytes regarding the upregulation of the Cav3 channels.…”

Section: Resultsmentioning

confidence: 99%

“…BDNF specifically binds to the tropomyosin-related kinase receptor B (TrkB) and activates multiple intracellular signaling pathways in many different types of cells [ 14 ]. Recent emerging evidence suggests that BDNF is also required for the physiological and pathophysiological function in the heart [ 15 , 16 ]. Of note, several studies demonstrate that cardiac hypoxia/ischemia triggers the elevation of BDNF production in cardiomyocytes, suggesting variable roles of BDNF including for angiogenesis, contractility, anti-apoptosis, anti-oxidative, reducing infarction area, and mitochondrial biogenesis [ 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Enhanced BDNF Actions Following Acute Hypoxia Facilitate HIF-1α-Dependent Upregulation of Cav3-T-Type Ca2+ Channels in Rat Cardiomyocytes

et al. 2021

Brain-derived neurotrophic factor (BDNF) has recently been recognized as a cardiovascular regulator particularly in the diseased condition, including coronary artery disease, heart failure, cardiomyopathy, and hypertension. Here, we investigate the role of BDNF on the T-type Ca2+ channel, Cav3.1 and Cav3.2, in rat neonatal cardiomyocytes exposed to normoxia (21% O2) and acute hypoxia (1% O2) in vitro for up to 3 h. The exposure of cardiomyocytes to hypoxia (1 h, 3 h) caused a significant upregulation of the mRNAs for hypoxia-inducible factor 1α (Hif1α), Cav3.1, Cav3.2 and Bdnf, but not tropomyosin-related kinase receptor B (TrkB). The upregulation of Cav3.1 and Cav3.2 caused by hypoxia was completely halted by small interfering RNA (siRNA) targeting Hif1a (Hif1a-siRNA) or Bdnf (Bdnf-siRNA). Immunocytochemical staining data revealed a distinct upregulation of Cav3.1- and Cav3.2-proteins caused by hypoxia in cardiomyocytes, which was markedly suppressed by Bdnf-siRNA. These results unveiled a novel regulatory action of BDNF on the T-type Ca2+ channels expression through the HIF-1α-dependent pathway in cardiomyocytes.