Scientists have made a remarkable discovery about a long non-coding RNA called NORAD and its role in preventing a harmful type of cell death called ferroptosis in the context of coronary artery disease (CAD). Their findings suggest that elevated levels of NORAD in the blood of CAD patients can help maintain the health and function of endothelial cells, which line the inside of blood vessels. This is a significant breakthrough, as endothelial dysfunction is a key driver of atherosclerosis, the buildup of plaque in arteries that can lead to heart attacks and strokes. By better understanding how NORAD regulates endothelial cell growth and protects against ferroptosis, researchers may be able to develop new therapies to prevent and treat cardiovascular disease.
Elevated NORAD Levels in CAD Patients
The researchers began by measuring the levels of NORAD in the plasma (the liquid part of blood) of 75 CAD patients and 76 healthy controls. They found that NORAD levels were significantly higher in the CAD patients compared to the control group, suggesting NORAD could be a useful biomarker for diagnosing CAD.
NORAD Regulates Endothelial Cell Function
To understand how NORAD might be involved in the development of CAD, the researchers investigated its effects on human umbilical vein endothelial cells (HUVECs) in the laboratory. When they suppressed NORAD expression in these cells, they observed several notable changes:
– Cell cycle arrest: NORAD knockdown caused the endothelial cells to get stuck in the G0/G1 phase of the cell cycle, preventing them from progressing to the S phase and dividing.
– Reduced cell migration: Endothelial cell migration, an important process for maintaining the integrity of blood vessel walls, was significantly impaired when NORAD was silenced.
– Increased oxidative stress: Levels of reactive oxygen species (ROS), which can damage cells, were elevated in the NORAD-deficient endothelial cells.
These findings suggest that NORAD plays a critical role in regulating the proliferation, migration, and oxidative state of endothelial cells, all of which are crucial for maintaining healthy blood vessels.
NORAD Protects Endothelial Cells from Ferroptosis
The researchers then explored the mechanism by which NORAD exerts its protective effects on endothelial cells. They found that suppressing NORAD led to a significant increase in the proportion of endothelial cells undergoing early apoptosis, a precursor to a form of regulated cell death called ferroptosis.
Ferroptosis is characterized by the accumulation of toxic lipid peroxides and the depletion of antioxidants, such as glutathione (GSH) and the enzyme glutathione peroxidase 4 (GPX4). The researchers observed that NORAD knockdown resulted in:
– Decreased GSH levels
– Reduced expression of GPX4, FTH1, and other proteins involved in ferroptosis regulation
– Increased lipid peroxidation
– Disruption of mitochondrial function
These changes all contribute to a pro-ferroptotic cellular environment, suggesting that NORAD plays a crucial role in protecting endothelial cells from this destructive form of cell death.
NORAD Regulates the miR-106a/CCND1 Axis
The researchers further investigated the mechanisms by which NORAD exerts its protective effects on endothelial cells. They found that NORAD acts as a “sponge” for a microRNA called miR-106a, which normally inhibits the expression of the cell cycle regulator CCND1 (also known as cyclin D1).
By sequestering miR-106a, NORAD allows CCND1 to be expressed at higher levels, promoting endothelial cell proliferation and preventing cell cycle arrest. This suggests that the NORAD-miR-106a-CCND1 axis is a critical pathway through which NORAD maintains endothelial cell health and function.
Implications and Future Directions
This study provides valuable insights into the role of NORAD in the development of CAD and atherosclerosis. By understanding how NORAD regulates endothelial cell function and protects against ferroptosis, researchers may be able to develop new therapies that target this long non-coding RNA or its downstream effectors.
Additionally, the findings suggest that NORAD could be a useful biomarker for the early detection of CAD, potentially allowing for earlier intervention and prevention of cardiovascular events. Further research is needed to fully elucidate the complex interplay between NORAD, endothelial cell biology, and the progression of atherosclerosis.
Author credit: This article is based on research by Tao He, Junxing Pu, Haijing Ge, Tianli Liu, Xintong Lv, Yu Zhang, Jia Cao, Hong Yu, Zhibing Lu, Fen Du.
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