The lower threshold plasma 25-hydroxy vitamin D (25(OH)D) level for optimal cardiovascular health is unclear, whereas the toxicity threshold is less clear. The aim of this study was to examine the cardiovascular-vitamin D dose-response curve in a normal rat model. Doses of cholecalciferol ranged from deficiency to toxic levels (equivalent to human doses of 0, 0·015, 0·25 and 3·75mg/d) for 4 weeks, and then cardiovascular health was examined using blood pressure telemetry and high-resolution ultrasound in normal male rats (n 16/group, 64 rats total). After 1 month, only the 0·25mg/d group had plasma 25(OH)D that was within current recommended range (100-125 nmol/l), and all groups failed to change plasma Ca or phosphate. Systolic blood pressure increased significantly (10-15 mmHg) in the rat groups with plasma 25(OH)D levels at both 30 and 561 nmol/l (groups fed 0 and 3·75mg/d) compared with the group fed the equivalent to 0·015mg/d (43 nmol/l 25(OH)D). Although not significant, the group fed the equivalent to 0·25mg/d (108 nmol/l 25(OH)D) also showed a 10 mmHg increase in systolic blood pressure. Carotid artery diameter was significantly smaller and wall thickness was larger, leading to higher peak carotid systolic blood velocity in these two groups. Despite these vascular changes, cardiac function did not differ among treatment groups. The key finding in this study is that arterial stiffness and systolic blood pressure both showed a U-shaped dose-response for vitamin D, with lowest values (best cardiovascular health) observed when plasma 25(OH)D levels were 43 nmol/l in normal male rats.
Toll‐like receptors (TLRs) are conserved immune receptors that play critical roles in innate immunity and are known as “gate keepers” of immune system. TLR10 is identified as type 1 plasma membrane protein but the identity of its ligand remains unclear. Till date, no data available on tissue and cell specific expression of TLR10 in normal and inflamed lungs of domestic animal species, and rat, which is commonly used as a model to study human diseases. First, we used homologous sequence alignment of published sequences of TLR10 from cattle, pig, dog, chicken and rat and the peptide alignment with antibody sequence to determine that a commercially available TLR10 antibody may be suitable for detection of TLR10. Western blotting of total lung protein extracts from cattle, dog, pig and chicken showed a band in 85‐ 100kDa region indicating the TLR10 protein. The immunohistochemistry, immunoelectron microscopy and confocal microscopy data show TLR10 expression in vascular endothelium and smooth muscle actin of control and inflamed animals. Further, we detected that basal expression of TLR10 in bovine neutrophil is altered upon treatment with E. coli lipopolysaccharide. These data show TLR10 expression in the lungs of these mammalian species and that activation of bovine neutrophils alters the expression of TLR10
TLR10 is a member of TLRs that recognize pathogen-associated molecules and play critical roles in host defense. However, very little is known about the expression and function of TLR10. We found TLR10 expression in vascular endothelium of normal and inflamed lungs from chickens and humans. Western blots showed increased TLR10 protein in lungs of chicken infected with E. coli or Adenovirus. Human neutrophils challenged with E. coli lipopolysaccharide (LPS) showed decreased total TLR10 protein and surface expression in 90 minutes. Confocal microscopy detected cytosolic and nuclear TLR10 in normal neutrophils. Upon activation with LPS, TLR10 colocalized with TLR4, flotallin-1, a lipid raft marker, and EEA-1, an early endosomal marker, to suggest the cycling to endocytic compartments. TLR4 neutralization reduced cytoplasmic localization of TLR10 in neutrophils. Depletion of reactive oxygen species (ROS) with FCCP in LPS-treated neutrophils reduced p65 nuclear translocation and TLR10 expression. Single cell video imaging of live LPS-activated human neutrophils showed the translocation of TLR10 to the leading edge and siRNA-mediated silencing of TLR10 in HL-60 cell line reduced their chemotaxis towards fMLP. We conclude that TLR10 expression is modulated via TLR4 signalling and ROS production, and that TLR10 participates in neutrophil chemotaxis. Altered TLR10 expression in activated neutrophils and inflamed lungs suggests a role for this receptor in lung inflammation.
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