Calcitriol blunts the deleterious impact of advanced glycation end products on endothelial cells

Abstract

Advanced glycation end products (AGEs), which are elevated in diabetic and uremic patients, may induce vascular dysfunctions, and calcitriol may improve the cardiovascular complications. Therefore, we examined whether calcitriol may modify the endothelial response to AGEs stimulation. Knowing the importance of nuclear factor-kappaB in endothelial inflammatory responses, the effect of AGEs and calcitriol on this pathway was also studied. Calcitriol was added to endothelial cells previously incubated with AGE-human serum albumin (HSA). AGE-HSA induced a decrease in endothelial nitric oxide synthase (eNOS) mRNA expression and enzyme activity. Addition of calcitriol to AGE-HSA-treated endothelial cells improved the decreased action of AGEs on the eNOS system. AGE-HSA increased the AGEs receptor mRNA and protein, which were both blunted by calcitriol. The parallel elevation of interleukin-6 mRNA in the presence of AGE-HSA was also blunted by calcitriol. The NF-kappaB-p65 DNA binding activity was enhanced and associated with a decrease in inhibitor kappaBalpha (IkappaBalpha) and an increase in phosphorylated (p)-IkappaBalpha levels. Addition of calcitriol blunted the AGEs-induced elevation of NF-kappaB-p65 DNA binding activity, a phenomenon related to an increased expression of IkappaBalpha. This increase was correlated to declined p-IkappaBalpha levels. The present results support the concept that calcitriol may act as a vascular protective agent counteracting the probable deleterious actions of AGEs on endothelial cell activities.

Impact of vitamin D supplementation on endothelial and inflammatory markers in adults: A systematic review

“…Some of the included study participants had T2DM and others were uremic patients. Hence, vitamin D acting through VDR may have improved endothelial dysfunction by hindering the damaging effects of advanced glycation end products (which have been reported to be increased in diabetic and uremic patients) by reducing the expression of genes such as IL-6, and IL-8 involved in the advanced glycation end products-activated inflammatory pathway [49].…”

The association between low 25-hydroxyvitamin D and increased aortic stiffness

“…16 There are also non-calciotropic mechanisms, which may explain the association between vitamin D and arterial stiffness: calcitriol probably directly modulates the vascular smooth muscle cell production 17 and reduces the adverse impact of advanced glycation end-products on vascular aging. 18 There are only few clinical studies dealing with the association between vitamin D and large artery properties, and most of them were done in patients with end-stage renal disease. London et al 19 reported that increased arterial stiffness measured by PWV was significantly associated with vitamin D deficiency in end-stage renal disease patients.…”

Role of Vitamin D in Atherosclerosis

“…AA 36,37 Finally, calcitriol may also act as a vascular protective agent counteracting the deleterious effects of advanced glycation end products on endothelial function. 38 Increased concentrations of glucose and advanced glycation end products acting through its receptor of advanced glycation end products can induce the expression of proinflammatory molecules by ECs. Calcitriol acting via VDR has been found to decrease the expression of genes involved in advanced glycation end products-activated inflammatory pathway such as RAGE, IL-6, and IL-8 through an NF-κB-mediated mechanism.…”