NOXICTUS

Artículos científicos

• Marqués, J.; Fernández-Irigoyen, J.; Ainzúa, E.; Martínez-Azcona, M.; Cortés, A.; Roncal, C.; Orbe, J.; Santamaría, E.; Zalba, G. NADPH Oxidase 5 (NOX5) Overexpression Promotes Endothelial Dysfunction via Cell Apoptosis, Migration, and Metabolic Alterations in Human Brain Microvascular Endothelial Cells (hCMEC/D3). Antioxidants 2022, 11, 2147. https://doi.org/10.3390/antiox11112147

Strokes are the leading cause of death for women and the second for men, according to the Navarre Institute of Public Health and Labour.

As of today, all the mechanisms that participate in vascular occlusion in general, and in ischemic strokes in particular, are not fully known. Additionally, the search for new markers and therapeutic focuses for that pathology is a high priority in clinical practice.

Oxidative stress plays a key role in cerebrovascular accidents, and specifically in Ischemic strokes. An excess in the production of reactive spices of the oxygen generated by the activation of the NADPH oxidase family (NOX) compromises the function of the endothelium because oxidation processes of macromolecules, metalloproteinase activation and cellular senescence are promoted. The preliminary findings have shown that oxidative stress alters the homeostasis of the endothelium and promotes the thrombotic process.

NADPH oxidase 5 (NOX5) is present in different cell types of the vascular wall, including endothelial cells, and its expression increases with the development of the vascular injury, even though its involvement in ischemic strokes has not been fully characterised. In that context, this project put forth the hypothesis that oxidative stress mediated by activation of NOX5 would favour inflammation and vascular damage processes and, insofar as the latter, would promote the formation of thrombi and the development of an ischemic stroke.

The primary goal of the project was to characterise the role of NOX5 in the development of an ictus. To achieve that we set out to do a project that included the development of suitable experimental models, the use of new diagnostic (-omics) and therapeutic tools, with the ultimate goal of being able to transfer the experimental results to clinical practices for ictus.
In greater detail, the specific goals were: (1) create an in vitro cellular model that would recapitulate the blood-brain barrier, (2) create a transgenic rat that over-expresses the human NOX5 gene specifically in the endothelium and do a preclinical study in different ictus models, and (3) do a clinical study in a group of healthy asymptomatic subjects and a group of symptomatic patients with a stroke.

The results of the study have provided new knowledge about the molecular mechanisms involved in the regulation and activation of NOX5, and about its relevance as a diagnostic and therapeutic target for ischemic strokes. Along those lines, the results obtained confirm the significant role of gender in the risk of thrombosis, which interacts significantly with a more pro-oxidant genotype. Furthermore, the results of the project will make it possible to implement new, more personalised protocols in the near future that help prevent the development of strokes.

Along those lines, all society and the society of Navarre in particular, will be able to benefit from the results obtained. It should be highlighted that the project was backed from the beginning by ADACEN, a unique SINAI agent, whose members could be the first to benefit from the results of the project, especially the ones that make it possible to use new protocols for managing their condition, in particular, by lowering the risk of stroke recurrence. Lastly, carrying out this collaborative project helped the consolidation of the (public and private) centres involved, reinforcing their excellence and facilitating the creation of new future collaborations in this field.