Increased Endothelin-1 Responsiveness in Human Coronary Artery Smooth Muscle Cells Exposed to 1,25-Dihydroxyvitamin D3.
ABSTRACT Low blood concentrations of 25-hydroxyvitamin D(3) are associated with increased mortality, while some studies suggest improved cardiovascular outcomes with vitamin D(3) supplementation in chronic kidney disease. However, the physiological effects of vitamin D(3) on the cardiovascular system remain poorly understood making it difficult to determine whether vitamin D(3) supplementation might provide cardiovascular benefit or even cause harm. Thus, here we investigated the effects of chronic 1,25-dihydroxyvitamin D(3) treatment on intracellular signaling in human coronary artery smooth muscle cells (HCASMCs) and found that 1,25-dihydroxyvitamin D(3) significantly potentiated endothelin (ET-1) signaling. Specifically, 1,25-dihydroxyvitamin D(3) (24-hr pretreatment) caused a >3-fold enhancement in both ET-1-induced intracellular calcium mobilization and extracellular signal-regulated kinase (ERK) activation. This 1,25-dihydroxyvitamin D(3)-elicited signaling enhancement was not observed for either vasopressin or carbachol. Using ETR isoform-selective antagonists, ETRA was found to be primarily responsible for the 1,25-dihydroxyvitamin D(3)-induced ET-1 responsiveness and yet ETRA mRNA expression and protein abundance were unaltered following 1,25-dihydroxyvitamin D(3) treatment. While there was an increase in ETRB mRNA expression in response to 1,25-dihydroxyvitamin D(3), the protein abundance of ETRB was again unchanged. Finally, ETRA/ETRB heterodimerization was not detected in HCASMCs in either the absence or presence of 1,25-dihydroxyvitamin D(3). Together, these data show for the first time, that 1,25-dihydroxyvitamin D(3) enhances endothelin responsiveness in HCASMCs and that the effect is mediated through ETRA.
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ABSTRACT: Despite the presence of vitamin D receptor (VDR) in endothelial cells, the effect of vitamin D on endothelial function is unknown. An unbalanced production of vasoactive endothelial factors, such as nitric oxide (NO) or endothelin-1 (ET-1), results in endothelial dysfunction, which can alter the normal cardiovascular function. Present experiments were devoted to assess the effect of active vitamin D (calcitriol) on the synthesis of endothelial vasoactive factors. Results: In cells, calcitriol increased ET-1 and NO productions, measured by ELISA and fluorimetric assay, respectively. Calcitriol also increased endothelin-converting enzyme-1 (ECE-1) and endothelial-nitric oxide synthase (eNOS) activities, their mRNA (qPCR), protein expressions (Western-blot) and promoter activities (transfection assays). Calcitriol did not change prepro-ET-1 mRNA. The effect was specific of VDR activation because when VDR was silenced by siRNA, the observed effects disappeared. Mechanisms involved in each up-regulation differed. ECE-1 up-regulation depended on AP-1 activation, whereas, eNOS up-regulation depended directly on VDR activation. To evaluate the in vivo consequences of acute calcitriol treatment, normal Wistar rats were treated with a single i.p injection of 400 ng/kg of calcitriol and sacrificed 24h later. Results confirmed those observed in cells: production and expression of both factors were increased by calcitriol. Besides, calcitriol-treated rats showed a slight rise in mean blood pressure, which decreased when pretreated with FR-901533, an ECE-1 antagonist. Conclusions: Calcitriol increases the synthesis of both ET-1 and NO in endothelial cells. However, the ET-1 up-regulation seems to be biologically more relevant, as animals acutely treated with calcitriol show slight increases of blood pressure.AJP Endocrinology and Metabolism 10/2014; · 4.09 Impact Factor
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ABSTRACT: Since the discovery that the enzyme catalyzing the synthesis of the most active natural vitamin D metabolite (calcitriol) and the vitamin D-specific receptor (VDR) were expressed in a wide range of tissues and organs, not only involved in the mineral metabolism (MM), there has been increasing interest on the putative 'non classical' roles of vitamin D metabolites, particularly on their possible effects on the cardiovascular (CV) system. These hypothetical CV effects of vitamin D gained particular interest in the nephrology field, given the high prevalence of CV disease in patients affected by either acute or chronic kidney diseases. However, notwithstanding a huge amount of experimental data suggesting a possible protective role of vitamin D on the CV system, the conclusions of two recent meta-analyses from the Cochrane group and a recent statement from the Institute of Medicine, based on a complete revision of the available data, concluded that there is no clear evidence for a role of vitamin D other than that strictly associated with bone health. However, a continuous and increasing flow of new studies still continues to add information on this topic. In the present review, we have tried to critically address the data added on this topic in the last 2 years, considering separately the experimental, observational, and intervention studies that have appeared in PubMed in the last 2 years, discussing the data providing proof, pro or contra, the involvement of vitamin D in CV disease, both in the absence or presence of kidney function impairment.American Journal of Cardiovascular Drugs 10/2013; 14(1). · 2.20 Impact Factor