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

Abstract

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.

Negative relationship between brain-derived neurotrophic factor (BDNF) and attention: A possible elevation in BDNF level among high-altitude migrants

“…The negative association was explained by the fact that the higher expression of BDNF can cause overall membrane hyperexcitability in brain structures, and the hyperexcitability is toxic to normal plasticity ( 56 ) and further leads to abnormalities in brain function. However, this explanation is not suitable for the negative association between BDNF and attention with a long-term exposure of hypoxia, as it's been reported that elevation in BDNF level often occurs when the exposure time to HA is short ( 37 ). Long-term exposure to hypoxia, as previous studies have observed that BDNF levels were significantly decreased after an exposure of hypoxia of around 2.3 years compared to sea level ( 39 ).…”

“…BDNF, a prominent factor associated with attention function, may also play a role in the inconsistency of attention variation in HA. BDNF level can be reportedly elevated by both acute hypoxia and intermittent hypobaric hypoxia to promote neurogenesis through BDNF-mediated signaling ( 1 , 37 , 38 ), while chronic hypoxia can result in a decrease in BDNF level ( 39 ). An increase in BDNF can improve attention impairment and some studies have found that increased BDNF levels are associated with inattentive problems ( 40 , 41 ).…”

Protein Kinase C Regulates Expression and Function of the Cav3.2 T-Type Ca2+ Channel during Maturation of Neonatal Rat Cardiomyocyte

“…Neonatal rat cardiomyocytes were prepared as described previously [ 10 , 11 ]. Neonatal ventricular myocytes were prepared from 2-8-days-old Wistar rats and maintained at 37 °C under 5% CO 2 in Dulbecco’s modified Eagle’s medium (DMEM) that was supplemented with 10% fetal bovine serum for 24 h, followed by an additional 24 h incubation in DMEM with or without protein kinase inhibitor, or a protein kinase activator (see the figure insets).…”