Calcitriol Supplementation Ameliorates Microvascular Endothelial Dysfunction in Vitamin D-Deficient Diabetic Rats by Upregulating the Vascular eNOS Protein Expression and Reducing Oxidative Stress.

Chee Lee Wee,Kirnpal Kaur Banga Singh,Siti Safiah Mokhtar,Aida Hanum Ghulam Rasool,Sahran Yahaya,Susan Wai Sum Leung,Rajeshwary Ghosh

doi:10.1155/2021/3109294

Abstract

Diabetes mellitus contributes to macro- and microvascular complications, leading to adverse cardiovascular events. This study examined the effects of vitamin D deficiency on the vascular function and tissue oxidative status in the microcirculation of diabetic rats and to determine whether these effects can be reversed with calcitriol (active vitamin D metabolite) supplementation. Streptozotocin-induced diabetic rats were fed for 10 weeks with control diet (DC) or vitamin D-deficient diet without (DD) or with oral calcitriol supplementation (0.15 μg/kg) in the last four weeks (DDS) (10 rats each group). A nondiabetic rat group that received control diet was also included (NR). After 10 weeks, rats were sacrificed; mesenteric arterial rings with and without endothelium were studied using wire myograph. Western blotting of the mesenteric arterial tissue was performed to determine the protein expression of endothelial nitric oxide synthase (eNOS) enzyme. Antioxidant enzyme superoxide dismutase (SOD) activity and oxidative stress marker malondialdehyde (MDA) levels in the mesenteric arterial tissue were also measured. The DC group had significantly lower acetylcholine-induced relaxation and augmented endothelium-dependent contraction, with reduced eNOS expression, compared to NR rats. In mesenteric arteries of DD, acetylcholine-induced endothelium-dependent and sodium nitroprusside-induced endothelium-independent relaxations were lower than those in DC. Calcitriol supplementation in DDS restored endothelium-dependent relaxation. Mesenteric artery endothelium-dependent contraction of DD was greater than DC; it was not affected by calcitriol supplementation. The eNOS protein expression and SOD activity were significantly lower while MDA levels were greater in DD compared to DC; these effects were not observed in DDS that received calcitriol supplementation. In conclusion, vitamin D deficiency causes eNOS downregulation and oxidative stress, thereby impairing the vascular function and posing an additional risk for microvascular complications in diabetes. Calcitriol supplementation to diabetics with vitamin D deficiency could potentially be useful in the management of or as an adjunct to diabetes-related cardiovascular complications.

Highlights

Diabetes mellitus (DM), which is characterized by chronic hyperglycemia resulting from defective insulin secretion and/or insulin action [1], is a major growing threat to public health
Nondiabetic rats (NR) had significantly higher body weight at the end of the study compared to diabetic groups
Supplementation with calcitriol for 4 weeks in DDS did not improve vitamin D levels when compared to deficient diet without (DD) and remained significantly lower than DC

Summary

Introduction

Diabetes mellitus (DM), which is characterized by chronic hyperglycemia resulting from defective insulin secretion and/or insulin action [1], is a major growing threat to public health. This disease ranks as the world top ten leading causes of death in year 2019 and constitutes 11.3% of global allcause mortality, causing 4.2 million deaths globally in year 2019 [2]. Cardiovascular diseases (CVD) are the major contributor to morbidity and mortality in diabetics [3]. It is critical to recognise and treat this devastating disease early to delay or even prevent serious diabetes-related secondary cardiovascular complications

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