Potential therapeutic target could halt PAH progression, rat study finds
Suppressing Jagged-2 protein reduced inflammation, oxidative stress in rats
Researchers have pinpointed Jagged-2, a signaling protein, as a potential therapeutic target for slowing or halting the progression of pulmonary arterial hypertension (PAH), based on a rat study.
Suppressing Jagged-2 in a rat model reversed various processes that drive PAH progression, including inflammation and oxidative stress, a form of cellular damage caused by highly reactive oxygen-containing molecules.
The rat study, “Unveiling the role of Jagged2 in hypoxic pulmonary arterial hypertension: A NOX2-mediated pathway,” was published in the Journal of Cell Communication and Signaling.
Suppressing Jag2 in rats reversed effects of hypoxia
In PAH, the narrowing of the pulmonary arteries that pass through the lungs is driven by pulmonary vascular remodeling — the uncontrolled growth of cells lining blood vessels, particularly pulmonary artery smooth muscle cells (PASMCs). This restricts blood flow, raises blood pressure, and triggers disease symptoms.
Current treatments for PAH, such as medications, surgery, and lung transplant, are limited in that they mainly relieve symptoms and prolong survival rather than halt or reverse disease progression. Their effectiveness is especially limited in severe cases, underscoring the need for new therapeutic approaches.
Recently, research has increasingly focused on developing targeted therapies aimed at specific molecular and signaling pathways involved in PAH progression.
To that end, a research team in China analyzed gene expression (activity) data from rat lung tissue that had been exposed to low oxygen, or hypoxia, to induce PAH conditions.
A total of 288 genes in the hypoxia group showed significant changes in behavior compared with the control samples. These genes were related to immune activity, cell death, and response to oxidative stress.
After running these data through a series of computer algorithms, the activity of the Jag2 gene, which encodes the signaling protein Jagged-2 (Jag2), was found to be significantly higher in the hypoxia group. When PASMCs were exposed to hypoxia for different lengths of time, Jag2 expression increased significantly with longer exposure time, confirming the computer-based findings.
These findings indicate that the Jag2/NOX2/ROS pathway plays a significant role in the pathological [disease] progression of PAH, making Jag2 a potential therapeutic target.
Further experiments demonstrated that Jag2 regulated the growth, migration, and survival of PASMCs, thus contributing to the pulmonary artery narrowing and cellular damage associated with PAH. Jag2 does this by activating an enzyme called NOX2, which generates reactive oxygen species (ROS). These highly reactive chemicals are produced during metabolism and lead to oxidative stress.
The researchers then created a rat model of PAH via hypoxia exposure. Some rats also received an engineered adeno-associated virus designed to selectively reduce Jag2 expression, thereby mimicking the effects of a potential Jag2-targeted therapy.
In PAH rats, hypoxia triggered an influx of macrophages, a type of immune cell; increased levels of pro-inflammatory signaling proteins, such as TNF-alpha and interleukin-6, which orchestrate immune responses; and resulted in greater oxidative stress in the pulmonary arteries. Apoptosis — the body’s process of eliminating old, damaged, or unneeded cells — was also suppressed in PAH rats.
In comparison, lowering Jag2 activity in hypoxic PAH rats reversed these effects, as indicated by reduced inflammation markers and oxidative stress, while promoting apoptosis.
“These findings indicate that the Jag2/NOX2/ROS pathway plays a significant role in the pathological [disease] progression of PAH, making Jag2 a potential therapeutic target,” the researchers concluded.
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