Vascular dysfunction in diabetes and metabolic syndrome:clinical biomarkers and experimental intervention

Metabolic Syndrome (MetS) and type 2 diabetes Mellitus (T2DM) are associated with comorbidities and increase the risk of cardiovascular mortality. Personalized cardiovascular risk stratification of MetS and exploring novel treatment strategies are vital. In this thesis we focus on endothelial dysfunction (ED) as an early event in the initiation and progression of MetS and T2DM and explored the role of GDF-15 (a cytokine related to the TGF-β family), mitochondrial reactive oxygen species, and sphingosine 1-phosphate. In healthy mice, inducing MetS by a high-fat diet resulted in increased adiposity and overexpression of the cytokine GDF-15, impairing vascular response. These data raised the question whether in diabetic conditions GDF-15 contributes to the progression of diabetic nephropathy and eventually could be used as a target of intervention. Indeed, in T2DM patients with nephropathy, plasma GDF-15 concentrations proved to be independently associated with renal endpoints, however adding GDF-15 into a clinical reference model for renal end point prediction did not improve the C-statistic and thus failed to additionally predict the progression of diabetic nephropathy. To slow the progression of cardiovascular disease and renal function loss in T2DM, we urgently need new therapies to counteract ED. We used a novel modified 6-chromanol compound, SUL-121, with promising cell protective effects that preserves cell viability due to its putative mitochondrial protective properties. We hypothesized that the antioxidant effects of SUL-121 could help combat oxidative stress damage in T2DM. We showed that SUL-121 proved to be a powerful and potent antioxidant, attenuating the progression of experimental diabetic nephropathy via a mechanism that reduces mitochondrial-induced oxidative stress and preserves vasorelaxation in the kidney. We also studied the preservative effects of Sul-121 in a rat model of transient focal cerebral ischemia. SUL-121 treatment was shown to be effective in preventing ED in the rat’s aorta. Moreover, SUL-121 alleviates cerebral ischemic damage and hemispheric swelling, an effect which was eventually mediated by preserving the NO component and endothelium-dependent vascular relaxation. Under physiologic conditions, analogs of sphingosine 1-phosphate (S1P) have been shown to exert pleiotropic effects on vascular function, with yet unknown mechanisms. We thus wondered whether or not FTY720 (S1P analog) might improve endothelial-dependent vasorelaxation. We observed a dual action of FTY720 treatment in normal rats: loss of vascular smooth muscle cell responsiveness associated with the compensatory synthesis of relaxing substances by the endothelial cells. The results of this work suggest that therapeutic interventions especially of mitochondria-induced oxidative stress pathways, could hold promise for future (pre-)clinical studies of MetS and T2DM to improve endothelial performance, reduce cardiovascular complications and preserve renal function