3 proteins identified as potential targets for PH treatment
Aging-related proteins may be key in PH progression, study finds
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Researchers using computational analyses of genetic data have identified three age-related proteins that may play key roles in the progression of pulmonary hypertension (PH), along with a small molecule that may be able to target these proteins.
“This work provides the first model for aging-related PH diagnosis and points out a promising small molecule drug candidate, providing possibilities for future translational research,” researchers wrote in the study, “Construction of an early diagnostic model for pulmonary hypertension based on aging-related signature genes and identification of potential therapeutic targets,” published in Scientific Reports.
PH is characterized by elevated pressure in the vessels that carry blood from the heart to the lungs, which strains the heart. Aging is one of the biggest risk factors for diseases that affect the heart. Generally, older people are more likely to have heart problems. But the biological mechanisms underlying this age-related risk are not fully understood.
“We hypothesized that aging-related signature genes may serve as effective biomarkers for the early diagnosis of pulmonary hypertension,” the team of scientists in China wrote, further noting that previous biomarker studies in PH have essentially focused on inflammation, mutations, or blood flow markers, “but these approaches often target late-stage progression rather than the underlying aging mechanisms, limiting their utility for early intervention.”
They conducted analyses of gene expression data — that is, which genes were more or less active in cells — aiming to identify genes whose activity is abnormal in people with PH. The scientists identified more than 600 genes and zeroed in on 20 associated with a cellular state known as senescence. Cellular senescence is the permanent cessation of cell growth; this cellular state is closely associated with aging.
Gene interaction is complex
One of the tricky parts of genetic research is that different genes interact in complex ways. If the activity of one gene changes, it may trigger changes in the activity of many other genes. The researchers used advanced computer algorithms to identify so-called hub genes, the genes primarily responsible for the widespread genetic dysregulation. They identified six senescence-related genes in their main dataset, and additional tests in other datasets showed three of them yielded consistent results.
The three identified genes, CBS, TLR8, and NQO1, each provide instructions for making proteins. Changes in gene activity mainly translate into altered protein levels. Data suggested that PH patients tend to have low levels of the CBS, TLR8, and NQO1 proteins. Studies in cell models showed results consistent with the computer-based analyses.
Of the two proteins with the most notable decreases in PH, the team said that low TLR8 may reflect an immune response to chronic inflammation, whereas low NQO1 may imply suppression of antioxidant defenses.
Since the data pointed to the CBS, TLR8, and NQO1 proteins as key players in PH, the researchers ran computational analyses looking for small molecules that might be able to target these proteins. This revealed a molecule called TUL-XXI039, which the computer models indicated is able to interact with all three proteins in a stable manner and has the potential to reverse PH-associated gene expression activity changes.
“Taken together, [genetic analyses and cell studies] support the roles of CBS, TLR8, and NQO1 in PH, while docking analyses suggest that TUL-XXI039 could function as a multi-target regulator, providing a potential new therapeutic strategy for PH,” the scientists concluded. They called for further experiments to validate these computer-based analyses.
