Resumen de Effect of sglt-2 inhibition in abdominal aortic aneurysm development. Role of rora in adipose tissue inflammation associated to obesity
Abdominal aortic aneurysm (AAA) is a localized dilatation of the abdominal aorta that predisposes to aortic rupture. The clinical approach to AAA is currently limited to surgical repair. Because of the high mortality rate associated with AAA, new effective therapeutic strategies are needed to prevent its progression. Beyond their glucose-lowering effects, recent studies have shown that SGLT-2 inhibitors have beneficial effects on vascular diseases such as atherosclerosis; however, the potential effects of SGLT-2 inhibition on AAA remain unknown. The aim of this Thesis was to evaluate the effect of the oral treatment with a SGLT-2 inhibitor, empagliflozin, on the progression of the AAA induced by angiotensin II (Ang II) in mice deficient in apolipoprotein E and its possible anti-inflammatory effects on human aortic endothelial cells and macrophages. Empagliflozin reduced the Ang II-induced increase in maximal suprarenal aortic diameter and diminished Ang II-induced elastin degradation, neovessel formation, macrophage infiltration and extracellular matrix degradation at the AAA lesion. Furthermore, p38 MAPK and NF-kB activation was reduced in the aortas of mice cotreated with empagliflozin. Studies in human aortic endothelial cells and macrophages showed that empagliflozin inhibited leukocyte-endothelial cell interactions and release of pro-inflammatory chemokines induced by TNFa. In conclusion, the pleiotropic beneficial effects that empagliflozin exerts to reduce AAA pathology suggest that therapeutic inhibition of SGLT-2 could be a viable strategy to limit AAA growth.
Morbid obesity is a chronic metabolic disease whose prevalence is increasing worldwide and the main concerns are linked to the wide spectrum of comorbidities related to this disorder such as type 2 diabetes mellitus. Inflammation governs adipose tissue (AT) dysfunction in obesity. Recently, RORa has been reported to be associated with inflammation and insulin resistance in animal studies, but its role in human obesity remains elusive. The next objective of this Thesis was to investigate the expression and function of RORa in AT from obese diabetic and non-diabetic patients. It was found that RORa expression was higher in omental AT than in subcutaneous AT and was positively associated with BMI and HOMA-IR. RORa expression was increased in omental AT from diabetic patients in comparation with non-diabetic AT samples. Pro-inflammatory chemokine release was higher in omental fat explants from diabetic patients than from non-diabetics, and this increase was diminished by RORa blockade. Inhibition of RORa improved PKB signalling, which was diminished in omental AT from diabetic patients. Under dynamic flow conditions, RORa inhibition prevented mononuclear cell attachment to human dysfunctional endothelial cells induced by TNFa. Therefore, RORa blockade could represent a potential therapy to prevent AT dysfunction and inflammation associated with insulin resistance in human obesity.
