Mechanisms Underlying Endothelin-1 Level Elevations Caused by Excessive Fluoride Exposure.

Area of Science:

• Environmental Toxicology
• Cardiovascular Physiology
• Cellular Signaling

Background:

• Excessive fluoride exposure is a growing environmental concern.
• Endothelin-1 (ET-1) plays a critical role in vascular homeostasis.
• The mechanisms linking fluoride exposure to ET-1 dysregulation are not fully understood.

Purpose of the Study:

• To investigate the mechanisms behind elevated endothelin-1 (ET-1) levels caused by excessive fluoride exposure.
• To elucidate the role of the ROS-RAS-MEK1/2-pERK1/2 pathway in this process.

Main Methods:

• Animal models (rabbits) and human umbilical vein endothelial cells (HUVECs) were used.
• Measurements included fluoride levels, plasma ET-1, aortic morphology, intracellular reactive oxygen species (ROS), and the RAS-MEK1/2-ERK1/2 pathway.
• Cells were treated with sodium fluoride (NaF) with or without U0126 (a MEK1/2 inhibitor).

Main Results:

• Fluoride exposure elevated plasma ET-1 levels and induced aortic hardening and endothelial vacuolation in rabbits.
• In HUVECs, fluoride increased ET-1, ET1 gene, and endothelin-converting enzyme-1 (ECE-1) expression, alongside elevated ROS and RAS activation.
• Inhibition of MEK1/2 with U0126 significantly reduced ECE-1 expression and ET-1 levels.

Conclusions:

• Excessive fluoride exposure induces endothelial damage and elevates ET-1 levels.
• The ROS-RAS-MEK1/2-pERK1/2 pathway is a key mediator of fluoride-induced ET-1 over-expression.
• These findings highlight a novel mechanism of fluoride toxicity on the cardiovascular system.