Increased endothelin-1 responsiveness in human coronary artery smooth muscle cells exposed to 1,25-dihydroxyvitamin D3

Absi M, Ward DT. Increased endothelin-1 responsiveness in human coronary artery smooth muscle cells exposed to 1,25-dihydroxyvitamin D3. Am J Physiol Cell Physiol 304: C666-C672, 2013. First published January 23, 2013; doi:10.1152/ajpcell.00349.2012.-Low blood concentrations of 25-hydroxyvitamin D3 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-h pretreatment) caused a more than threefold 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. With the use of endothelin receptor (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.