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 deficiency has been associated with cardiovascular dysfunction. We evaluated the role of the vitamin D receptor (VDR) in vascular endothelial function, a marker of cardiovascular health, at baseline and in the presence of angiotensin II, using an endothelial-specific knockout of the murine VDR gene. In the absence of endothelial VDR, acetylcholine-induced aortic relaxation was significantly impaired (maximal relaxation, endothelial-specific VDR knockout =58% vs. control=73%, p<0.05). This was accompanied by a reduction in eNOS expression and phospho-vasodilator-stimulated phosphoprotein levels in aortae from the endothelial-specific VDR knockout vs. control mice. While blood pressure levels at baseline were comparable at 12 and 24 weeks of age, the endothelial VDR knockout mice demonstrated increased sensitivity to the hypertensive effects of angiotensin II compared to control mice (after 1-week infusion: knockout = 155±15 mmHg vs. control = 133±7 mmHg, p<0.01; after 2-week infusion: knockout = 164±9 mmHg vs. control = 152±13 mmHg, p<0.05). By the end of two weeks, angiotensin II infusion-induced, hypertrophy-sensitive myocardial gene expression was higher in endothelial-specific VDR knockout mice (fold change compared to saline-infused control mice, ANP: knockout mice = 3.12 vs. control= 1.7, p<0.05; BNP: knockout mice= 4.72 vs. control= 2.68, p<0.05). These results suggest that endothelial VDR plays an important role in endothelial cell function and blood pressure control and imply a potential role for VDR agonists in the management of cardiovascular disease associated with endothelial dysfunction.

Members of the LIM homeodomain family of transcription factors have been shown to contribute to the regulated expression of the ␣-subunit of the glycoprotein family of hormones (1). The ability of the pituitary to secrete the gonadotropic hormones, follicle-stimulating hormone, and luteinizing hormone is crucial for normal reproductive function. The synthesis and secretion of the gonadotropins is regulated by the hypothalamic hormone, gonadotropin-releasing hormone (GnRH), 1 which acts to increase gonadotropin subunit mRNA levels (2-9) through effects at the transcriptional level (10, 11).LIM homeodomain factors appear to play a role in both basal and GnRH-stimulated expression of the glycoprotein hormone ␣-subunit gene (1, 12). Initial studies demonstrated that LIM homeodomain factor-2 (Lhx2, also designated LH-2) can bind to a pituitary-specific enhancer element designated the PGBE of the mouse ␣-subunit gene (1). Because both the PGBE and a separate, structurally distinct DNA element designated the GnRH-RE are required for GnRH responsiveness of the mouse glycoprotein hormone ␣-subunit promoter (12), the finding that Lhx2 binds to the PGBE implies that this LIM factor plays a role in transcriptional responses to GnRH. It has also been shown that a related LIM factor, Lhx3 (also designated pLIM or LIM3) can also enhance ␣-subunit gene expression (13). Targeted disruption of the Lhx3 gene in mouse results in loss of pituitary organogenesis (14), demonstrating that LIM factors also play an important developmental role in the formation of the pituitary.The specific role that the LIM domains play in transcriptional activation is somewhat unclear. The LIM domain, named for the genes of the first three members of the family, lin-11 (15), isl-1 (16), and mec-3 (17), is characterized by the presence of two zinc finger motifs that involve cysteine and histidine or aspartate residues that tetrahedrally coordinate a zinc atom (18,19). There is evidence that some LIM domains can inhibit DNA binding of the associated homeodomain (20 -22). This would suggest that the LIM domain may negatively regulate LIM factor activity. However, it is not clear that inhibition of DNA binding is a general phenomenon for LIM factors (23). Functional studies of Xlim-1 in Xenopus laevis have shown that deletion or mutation of the LIM domain of Xlim-1 results in the induction of secondary axis formation, whereas the wild type factor has no effect (24). This has been interpreted as evidence for a negative role for the LIM domain in regulating transcription. However, in the absence of more mechanistic information about Xlim-1 action, other interpretations are possible. In contrast to the view that LIM domains play a negative role in regulating DNA binding and transcription, some LIM factors have been shown to demonstrate synergistic transcriptional activation with other transcription factors (13,25).Recently, a putative co-activator was identified independently in several labs that binds to members of the LIM homeodomain protein family and nucle...

Effect of combining an ACE inhibitor and a VDR activator on glomerulosclerosis, proteinuria, and renal oxidative stress in uremic rats. Am J Physiol

Lipid accumulation in the heart is associated with obesity and diabetes mellitus and may play an important role in the pathogenesis of heart failure seen in this patient population. Stored triglycerides are synthesized by the enzyme diacylglycerol acyl transferase (DGAT). We hypothesized that forced expression of DGAT1 in the cardiac myocyte would result in increased lipid accumulation and heart dysfunction. A cardiac myocyte–selective DGAT1 transgenic mouse was created and demonstrated increased lipid accumulation in the absence of hyperglycemia, plasma dyslipidemia or differences in body weight. Over time, expression of DGAT1 in the heart resulted in the development of a significant cardiomyopathy. Echocardiography revealed diastolic dysfunction with increased early mitral inflow velocity to late mitral inflow velocity ratio and decreased deceleration time, suggesting a restrictive pattern in the transgenic mice. Moderate systolic dysfunction was also seen at 52 weeks. Histological analysis showed increased cardiac fibrosis and increased expression of procollagen type 1A, matrix metalloproteinase 2, and tissue inhibitor of matrix metalloproteinase 2 in the transgenic mice. Mitochondrial biogenesis was reduced in the transgenic hearts, as was expression of cytochrome c oxidase 1 and cytochrome c. Expression of key transcription factors important in the regulation of mitochondrial biogenesis were reduced. These findings suggest that triglyceride accumulation, in the absence of systemic metabolic derangement, results in cardiac dysfunction and decreased mitochondrial biogenesis.

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Vitamin D receptors (VDR) are found in cells throughout the cardiovascular system. A variety of experimental studies indicate that the liganded VDR may play an important role in controlling cardiac hypertrophy and fibrosis, regulating blood pressure, and suppressing the development of atherosclerosis. Some, but not all, observational studies in humans provide support for these experimental findings, raising the possibility that vitamin D or its analogs might prove useful therapeutically in the prevention or treatment of cardiovascular disease.

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