Expression of the Vitamin D Receptor Is Increased in the Hypertrophic Heart

Abstract

Abstract-The liganded vitamin D receptor (VDR) is thought to play an important role in controlling cardiac function.Specifically, this system has been implicated as playing an antihypertrophic role in the heart. Despite this, studies of VDR in the heart have been limited in number and scope. In the present study, we used a combination of real-time polymerase chain reaction, Western blot analysis, immunofluorescence, and transient transfection analysis to document the presence of functional VDR in both the myocytes and fibroblasts of the heart, as well as in the intact ventricular myocardium. We also demonstrated the presence of 1-␣-hydroxylase and 24-hydroxylase in the heart, 2 enzymes involved in the synthesis and metabolism of 1,25 dihydroxyvitamin D. VDR is shown to interact directly with the human B-type natriuretic peptide gene promoter, a surrogate marker of the transcriptional response to hypertrophy. Of note, induction of myocyte hypertrophy either in vitro or in vivo leads to an increase in VDR mRNA and protein levels. Collectively, these findings suggest that the key components required for a functional 1,25 dihydroxyvitamin D-dependent signaling system are present in the heart and that this putatively antihypertrophic system is amplified in the setting of cardiac hypertrophy. Recent studies suggest that VD3, in addition to stimulating absorption of intestinal calcium and promoting mineralization of bone osteoid, may play an important role in controlling cardiac hypertrophy. We have shown that VD3, as well as a number of nonhypercalcemic analogues, act in both atrial and ventricular myocytes 3,4 to inhibit the activation of phenotypic markers associated with hypertrophy in vitro. Endothelin (ET)-stimulated changes in fetal gene expression and promoter activity, cell size, and protein synthesis 4,5 are partially reversed by VD3 or its nonhypercalcemic analogues. Similar findings have been reported by others using the cultured cardiac HL-1 myocytes. 6 In animal studies, vitamin D deficiency in Sprague-Dawley rats leads to both hypertension and cardiac hypertrophy, 7 whereas treatment of Dahl salt-sensitive rats with the vitamin D analogue paricalcitol reverses cardiac hypertrophy in that model. 8 The VDR knockout mouse displays hypertension, cardiac hypertrophy with enlargement of individual myocytes, and elevations in atrial natriuretic peptide (ANP) expression. 9 However, the elevated blood pressure precludes assigning the liganded VDR a primary antihypertrophic role at the level of the cardiac myocyte. Although VDR has been identified microscopically 10 and functionally 11 in the heart, our understanding of the role of the liganded VDR in the maintenance of cardiac function remains incomplete.Although VDR is clearly present in the heart, we know little of the specific cell types in which it is expressed nor of the functional activities associated with the liganding of these receptors. In the present article, we demonstrate the presence of VDR-and VD3-dependent functional activity in both the

Vitamin D Status and Outcomes After Renal Transplantation

“…Of note, cardiomyocytes in rats express CYP27B1 and respond to cholecalciferol in vitro. 60 Studies from our group and other have already shown that cholecalciferol supplementation is a safe way to increase 25 (OH)D concentrations in kidney transplant recipients, but the small number of treated patients included in these studies and their short follow-up do not allow any conclusion on the effect of these treatments on kidney function. [61][62][63] Our results should encourage randomized controlled trials evaluating the effect of early cholecalciferol supplementation on renal allograft function and provide valuable information on the magnitude of the expected effects of such treatments on renal function and histologic features.…”

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

“…VDR has also been reported to regulate a variety of metabolic pathways, such as those involved in kidney diseases, immune responses and cancers. Moreover, recent evidence has demonstrated that VDR has a protective role in cardiac hypertrophy [152] , heart failure after cardiac remodeling [153] and MI/R injury [154] . LXRs have two receptor subtypes-LXRα (NR1H3) and LXRβ (NR1H2)-that exhibit different expression patterns and perform different functions [155] .…”

Vitamin D deficiency and myocardial diseases

“…Several studies have shown that cardiac myocytes express a functional VDR, which is primarily located in the nucleus and within, or adjacent to the t-tubules [5][6][7][8][9][10][11]. Cardiac fibroblasts also express the VDR.…”

“…Cardiac fibroblasts also express the VDR. Importantly, myocardial hypertrophy is associated with an increased expression of the VDR in cardiac myocytes as well as in cardiac fibroblasts [11]. Furthermore, it has been shown that cardiac myocytes and fibroblasts express the enzymes 1a-hydroxylase and 24-hydroxylase [11,12].…”

“…Importantly, myocardial hypertrophy is associated with an increased expression of the VDR in cardiac myocytes as well as in cardiac fibroblasts [11]. Furthermore, it has been shown that cardiac myocytes and fibroblasts express the enzymes 1a-hydroxylase and 24-hydroxylase [11,12]. Considering that the conversion of 25(OH)D to 1,25(OH)2D by 1a-hydroxylase in extrarenal tissues is mainly dependent on substrate availability, this latter finding suggests that, apart from 1,25(OH)2D plasma levels, the concentrations of circulating 25(OH)D levels might be a significant determinant of vitamin D effects in the myocardium.…”