Albumin, the most abundant protein in the blood, can play an active role in vascular inflammation when it undergoes little-explored chemical modification, known as uratylation. A new study shows, for the first time, that uratylated albumin activates endothelial cells and triggers inflammatory responses associated with the initial stages of vascular inflammation. Uratylation refers to protein modifications caused by products of uric acid oxidation.

The study was carried out by scientists from the Research Center for Redox Processes in Biomedicine - RIDC Redoxoma, led by Flavia Meotti at the Instituto de Química, Universidade de Sao Paulo (USP). The team investigated how uratylated albumin directly affects human vascular endothelial cells (HUVECs), seeking to understand its contribution to inflammatory processes in the vascular system. The results were published in the journal Redox Biochemistry and Chemistry.

“The main novelty of the study is demonstrating the effect that albumin uratylation in the body, triggering inflammatory responses,” says Railmara Pereira da Silva, first author of the article. “The modification of a protein leads to an exacerbated inflammatory state, which may be further aggravated under chronic situations. For us, it is very important to reveal these molecular mechanisms to better understand future clinical data.” The researcher conducted the work during her postdoctoral fellowship and is currently a researcher at the Center for Mass Spectrometry at Mannheim University of Applied Sciences in Germany.

According to Flavia Meotti, a key advance of the work is moving beyond clinical correlation. “When we detect increased levels of uric acid and its oxidation products, this suggests an association with a specific pathology, but it does not allow us to infer causality,” she explains. By demonstrating that modified albumin has pro-inflammatory activity, the study indicates that this alteration “is not just a simultaneous event, but may be directly involved in the pathological process.”

Although albumin uratylation had been described previously, its biological implications had not yet been demonstrated. “What this work does is precisely propose this modification in a molecule for which the functional consequences had never been explored,” Meotti adds.

The study

Albumin plays an essential role in the transport of a wide range of substances, including poorly water-soluble metabolites, ions, and exogenous compounds such as drugs, in addition to contributing to the maintenance of plasma osmotic balance. It is a protein highly susceptible to post-translational modifications, that is, chemical changes that occur after protein synthesis and can modify its structure and function.

In the study, researchers produced uratylated albumin in vitro and demonstrated that uratylation alters the structure of the protein. Subsequently, when human vascular endothelial cells were exposed to uratylated albumin, they observed increased monocyte adhesion compared with untreated cells, along with elevated expression of the adhesion molecule ICAM-1. These findings indicate an endothelial inflammatory response.

The increase in monocyte adhesion was accompanied by enhanced release of tumor necrosis factor alpha (TNF-α), an important pro-inflammatory cytokine involved in immune responses and systemic inflammation.

“If we follow the entire chain, oxidized uric acid modifies albumin; the modified albumin activates endothelial cells; these cells begin to express adhesion molecules that recruit inflammatory cells; and this recruitment leads to the release of pro-inflammatory cytokines. As a result, the organism enters an inflammatory state,” Railmara explains.

Atherosclerosis is one of the pathologies associated with this type of vascular inflammation. The experimental model used in the study, based on human endothelial cells, reproduces initial events occurring in the vessel walls, helping to understand how molecular alterations in the endothelium may contribute to the onset of the atherosclerotic process.

According to the researcher, the formation of these modifications does not depend on elevated plasma uric acid levels. Even at physiological concentrations, the presence of inflammation is sufficient for urate, the ionized form of uric acid, to be oxidized and generate these alterations. “The limiting factor is not the amount of circulating uric acid, but the presence of peroxidase enzymes capable of promoting its oxidation, especially myeloperoxidase, the main enzyme most closely associated with inflammation,” Railmara notes.

Uric Acid

Uric acid is an abundant metabolite in human plasma and can be readily oxidized under inflammatory conditions. Although it acts as an antioxidant in plasma, it has a dual role and also participates in pro-oxidant processes linked to inflammation and cardiovascular diseases.

“My doctoral project was precisely to search for uric acid oxidation products. During that period, we were able to elucidate an oxidant formed in inflammation, urate hydroperoxide, and, based on that, I started a postdoctoral fellowship to better understand this new molecule,” Railmara reports.

Flavia Meotti emphasizes the innovative nature of the study in identifying uratylation as a novel and relevant modification in plasma proteins. “Modifications caused by glucose or by glucose oxidation products are well described, associated with diseases, and even have diagnostic applications,” she says. “What we are now showing is a new modification, driven by uric acid, which may have a similar effect.”

In this study, the investigation focused on albumin, a protein highly abundant in plasma, and its effects within the vascular system, where uric acid levels are elevated. However, the researcher emphasizes that uratylation may not be limited to this target. “We may be facing new targets of this modification, with potential implications for other diseases beyond the vascular system.“

The article “Uratylated albumin activates endothelial cells to induce monocyte adhesion and the release of pro-inflammatory cytokines,” by Railmara Pereira da Silva, Beatriz Pereira da Silva, Antônio Paulo Siqueira Pratti, Bianca Dempsey, Caroline Dutra Lacerda, Gustavo Penteado Battesini Carretero, Álbert Souza Peixoto, Litiele Cezar Cruz, Camilla Adan, Iolanda Midea Cuccovia, and Flavia Carla Meotti, can be accessed here.