The Sulforaphane and pyridoxamine supplementation normalize endothelial dysfunction associated with type 2 diabetes

Abstract

In this study we investigate pyridoxamine (PM) and/or sulforaphane (SFN) as therapeutic interventions to determine whether activators of NFE2-related factor 2 (Nrf2) can be used in addition with inhibitors of advanced glycation end products (AGE) formation to attenuate oxidative stress and improve endothelial dysfunction in type 2 diabetes. Goto-kakizaki (GK) rats, an animal model of non-obese type 2 diabetes, were treated with or without PM and/or SFN during 8 weeks and compared with age-matched Wistar rats. At the end of the treatment, nitric oxide (NO)-dependent and independent vasorelaxation in isolated aorta and mesenteric arteries were evaluated. Metabolic profile, NO bioavailability and vascular oxidative stress, AGE and Nrf2 levels were also assessed. Diabetic GK rats presented significantly lower levels of Nrf2 and concomitantly exhibited higher levels of oxidative stress and endothelial dysfunction. PM and SFN as monotherapy were capable of significantly improving endothelial dysfunction in aorta and mesenteric arteries decreasing vascular oxidative damage, AGE and HbA1c levels. Furthermore, SFN + PM proved more effective reducing systemic free fatty acids levels, normalizing endothelial function, NO bioavailability and glycation in GK rats. Activators of Nrf2 can be used therapeutically in association with inhibitors of AGE and cross-linking formation to normalize endothelial dysfunction in type 2 diabetes.

Role of hydrogen sulfide in endothelial dysfunction: Pathophysiology and therapeutic approaches

“…The diabetic condition is characterized by low levels of NO at the vascular level due to oxidative stress and increased AGEs levels which contribute to the worsening of the endothelium functionality. Diabetic rats treated with SFN showed a significant decreased in vascular oxidative stress, and concomitantly increased NO bioavailability, partially explaining the beneficial effects on vascular function [122] .…”

Vascular Oxidative Stress: Impact and Therapeutic Approaches

“…Nrf2 is a transcription factor ubiquitously expressed in various tissues (including the vasculature) of human and animal models (Pereira et al, 2017; Suzuki and Yamamoto, 2017). It regulates the expression of several antioxidant and detoxification enzymes by binding to upstream antioxidant response elements (Ungvari et al, 2011; Juurlink, 2012).…”

Nrf2 as a Potential Mediator of Cardiovascular Risk in Metabolic Diseases

“…One proposed mechanism for the improvement of endothelial function following Nrf2 activation is the increased expression of a subunit of the BK (big potassium or large conductance, Ca 2+ -activated potassium) channel, the BK-β1, and its attenuated degradation (Lu et al, 2017), a process commonly accelerated by diabetes-induced oxidative stress (Li et al, 2017). Other mechanisms include reduced systemic and vascular oxidative stress as well as increased nitric oxide (NO) bioavailability (Liu et al, 2016; Pereira et al, 2017). Beyond this immediate homeostatic response, long-term consequences of Nrf2 activity have also been described as important culprits of micro-and macrovascular complications associated with diabetes.…”