NOVEL COMPOUNDS THAT SELECTIVELY TARGET NOX5 TO INTERFERE IN UNCONTROLLED ROS GENERATION.

CASTRO, CLAUDIA; QUESADA, ISABEL; ROSATO, GIULIANA; DE PAOLA, MATILDE

Mendoza

Jornada; V JORANDAS ACES Y JORNADAS DE HIPERTENSIÓN ARTERIAL DE CUYO; 2019

UNCuyo-Sociedad de Cardiología de Mendoza

The production of reactive oxygen species (ROS) occurs in health and disease, however the increased ROS release is often referred to as oxidative stress and it is an immediate consequence of up-regulation of pro-oxidant enzyme-induced ROS production and concomitant depletion of antioxidants. The pro-oxidant enzyme family NADPH oxidases (NOXs) is the main source of ROS in the vascular tissues. Increased ROS production and altered redox signaling in the vascular system have been implicated in the pathophysiology of cardiovascular diseases, including hypertension, and have been attributed, in part, to increased NOXs activity. This enzyme family consists of seven homologues (NOX1-5, DUOX1-2). NOX1,2,4, and NOX5 are expressed and functionally active in human vascular cells. While NOX1, 2, and 4 have been well characterized in models of cardiovascular disease, the role of NOX5 is less clear, probably due to lack of experimental traditional disease models since NOX5 is absent in rodents. Our general hypothesis propose that selective inhibition of NOX5 under proinflamatory conditions could improve endothelial function and decrease inflammation. The aim of this work was to assess different novel drugs which could interfere with NOX5 ROS production. To test this, dihydroethidium (DHE) was used to monitor ROS production by fluorescence microscopy in Human Aortic Smooth Muscle Cells (HASMC). Results showed an increased DHE fluorescence signal when HASMC were stimulated with TNF α and Angiotensin II, since they both promotes ROS production through NADPH oxidase activation. A decreased ROS production was found when stimulated HASMC were treated with selective inhibitors of NOX5, suggesting a proper inhibition of NOX5 system. In this study we attempted to set up a working model to research NOX5 biology and biochemistry in order to probe novel drugs that selectively target NOX5 to interfere in uncontrolled ROS generation. Although growing evidence indicate a role for NOX5 derived ROS in cardiovascular pathophysiology, the particular function remains unclear and further research is needed.