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Inhibition of TLR4 attenuates vascular dysfunction and oxidative stress in diabetic rats
Maria Alicia Carrillo-Sepulveda1,2, Kathryn Spitler3, Deepesh Pandey4
1Department of Physiology, Georgia Regents University, Augusta, GA, USA. mcarrill@nyit.edu.
Unlabelled:
Hyperglycemia-induced reactive oxygen species (ROS) production plays a major role in the pathogenesis of diabetic vascular dysfunction. However, the underlying mechanisms remain unclear. Toll-like receptor 4 (TLR4), a key component of innate immunity, is known to be activated during diabetes. Therefore, we hypothesize that hyperglycemia activates TLR4 signaling in vascular smooth muscle cells (VSMCs) that triggers ROS production and causes vascular dysfunction. Rat mesenteric VSMCs exposed to high glucose (25 mmol/l) increased TLR4 expression and activated TLR4 signaling via upregulation of myeloid differentiation factor 88 (MyD88). TLR4 inhibitor CLI-095 significantly attenuated elevated levels of ROS and nuclear factor-kappa B (NF-κB) activity in VSMCs exposed to high glucose. Mesenteric arteries from streptozotocin-induced diabetic rats treated with CLI-095 (2 mg/kg/day) intraperitoneally for 2 weeks exhibited reduced ROS generation and attenuated noradrenaline-induced contraction. These results suggest that hyperglycemia-induced ROS generation and NF-κB activation in VSMCs are at least, in part, mediated by TLR4 signaling. Therefore, strategies to block TLR4 signaling pathways pose a promising avenue to alleviate diabetic-induced vascular complications.
Key Messages:
High glucose-induced TLR4 activation in vascular smooth muscle cells. Inhibition of TLR4 attenuated high glucose-induced ROS production and NF-κB activity in VSMC. Suppression of TLR4 signaling attenuated mesenteric contraction in diabetic rat.
Insights
High glucose activates Toll-like receptor 4 (TLR4) in vascular cells, increasing reactive oxygen species (ROS) and causing dysfunction. Blocking TLR4 signaling reduces ROS and improves vascular function in diabetes.
Area of Science:
- Vascular Biology
- Immunology
- Metabolic Diseases
Background:
- Diabetic vascular dysfunction is linked to hyperglycemia-induced reactive oxygen species (ROS).
- The precise mechanisms driving this dysfunction, particularly the role of innate immunity, remain incompletely understood.
- Toll-like receptor 4 (TLR4) activation is implicated in diabetes, suggesting a potential role in vascular complications.
Purpose of the Study:
- To investigate the hypothesis that hyperglycemia activates Toll-like receptor 4 (TLR4) signaling in vascular smooth muscle cells (VSMCs).
- To determine if TLR4 activation triggers ROS production and contributes to vascular dysfunction in diabetes.
- To evaluate the therapeutic potential of inhibiting TLR4 signaling in diabetic vascular complications.
Main Methods:
- Exposed rat mesenteric VSMCs to high glucose conditions.
- Assessed TLR4 expression, myeloid differentiation factor 88 (MyD88) upregulation, and ROS production.
- Utilized a TLR4 inhibitor (CLI-095) to block signaling pathways.
- Evaluated nuclear factor-kappa B (NF-κB) activity in VSMCs.
- Administered CLI-095 to streptozotocin-induced diabetic rats and assessed mesenteric artery function.
Main Results:
- High glucose exposure increased TLR4 expression and MyD88 in VSMCs, indicating TLR4 pathway activation.
- CLI-095 treatment significantly reduced high glucose-induced ROS levels and NF-κB activity in VSMCs.
- In diabetic rats, CLI-095 administration attenuated ROS generation and noradrenaline-induced mesenteric artery contraction.
Conclusions:
- Hyperglycemia activates TLR4 signaling in VSMCs, contributing to ROS production and NF-κB activation.
- Inhibition of TLR4 signaling effectively mitigates hyperglycemia-induced ROS and NF-κB activity in VSMCs.
- Targeting TLR4 pathways represents a promising strategy for managing diabetic vascular complications.
