Amplification of lipotoxic cardiomyopathy in the VDR gene knockout mouse.

Previous studies demonstrated that the liganded vitamin D receptor (VDR) plays an important role in controlling cardiovascular homeostasis. Both the whole animal VDR gene knockout (VDR) and the myocyte-specific VDR gene deletion result in changes in cardiac structure and function. Clinical states associated with cardiac steatosis (obesity and diabetes mellitus) are also associated with low circulating 25 OH vitamin D levels.

Tie-2Cre mediated deletion of the vitamin D receptor gene leads to improved skeletal muscle insulin sensitivity and glucose tolerance.

A variety of studies have suggested that vitamin D may play a palliative role in improving insulin secretion and glucose tolerance. Endothelial cells of the microcirculation are thought to play an important role in regulating both insulin secretion and insulin sensitivity in target tissues. We have selectively deleted the vitamin D receptor (VDR) gene in endothelial cells of the murine vasculature.

Cardiac steatosis potentiates angiotensin II effects in the heart.

Lipid accumulation in the heart is associated with obesity and diabetes and may play an important role in the pathogenesis of heart failure. The renin-angiotensin system is also thought to contribute to cardiovascular morbidity in obese and diabetic patients. We hypothesized that the presence of lipid within the myocyte might potentiate the cardiomyopathic effects of ANG II in the cardiac diacylglycerol acyl transferase 1 (DGAT1) transgenic mouse model of myocyte steatosis.

Elimination of vitamin D receptor in vascular endothelial cells alters vascular function.

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% versus control=73%; P<0.

Vitamin D and the heart.

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.

Vitamin D: beyond bone.

In recent years, vitamin D has been received increased attention due to the resurgence of vitamin D deficiency and rickets in developed countries and the identification of extraskeletal effects of vitamin D, suggesting unexpected benefits of vitamin D in health and disease, beyond bone health. The possibility of extraskeletal effects of vitamin D was first noted with the discovery of the vitamin D receptor (VDR) in tissues and cells that are not involved in maintaining mineral homeostasis and bone health, including skin, placenta, pancreas, breast, prostate and colon cancer cells, and activated T cells. However, the biological significance of the expression of the VDR in different tissues is not fully understood, and the role of vitamin D in extraskeletal health has been a matter of debate.

Acute liver failure with thyrotoxicosis treated with liver transplantation.

Objective: We describe a young woman with previously undiagnosed thyrotoxicosis who presented with acute liver failure (ALF).

Methods: We present a case report and review the relevant literature.

Results: An extensive evaluation excluded possible causes of ALF other than thyrotoxicosis.

Liganded vitamin D receptor displays anti-hypertrophic activity in the murine heart.

Vitamin D and its analogs have been suggested to have palliative effects in the cardiovascular system. We have examined the effects of co-administration of the vitamin D receptor agonist, paricalcitol, on the hypertension, cardiac hypertrophy and interstitial fibrosis produced by chronic angiotensin II (AII) infusion. Administration of AII (800ng/kg/min) over a 14-day period resulted in increased blood pressure, myocyte hypertrophy, activation of the hypertrophic fetal gene program (atrial natriuretic peptide, B-type natriuretic peptide and alpha skeletal actin gene expression), increased expression of the pro-hypertrophic modulatory calcineurin inhibitor protein 1 (MCIP 1), and increased fibrosis with augmented procollagen 1 and 3 gene expression.

Expression of guanylyl cyclase-B (GC-B/NPR2) receptors in normal human fetal pituitaries and human pituitary adenomas implicates a role for C-type natriuretic peptide.

C-type natriuretic peptide (CNP/Nppc) is expressed at high levels in the anterior pituitary of rats and mice and activates guanylyl cyclase B receptors (GC-B/Npr2) to regulate hormone secretion. Mutations in NPR2/Npr2 can cause achondroplasia, GH deficiency, and female infertility, yet the normal expression profile within the anterior pituitary remains to be established in humans. The current study examined the expression profile and transcriptional regulation of NPR2 and GC-B protein in normal human fetal pituitaries, normal adult pituitaries, and human pituitary adenomas using RT-PCR and immunohistochemistry.

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

Angiotensin-converting enzyme (ACE) inhibitors ameliorate the progression of renal disease. In combination with vitamin D receptor activators, they provide additional benefits. In the present study, uremic (U) rats were treated as follows: U+vehicle (UC), U+enalapril (UE; 25 mg/l in drinking water), U+paricalcitol (UP; 0.

Cardiomyocyte-specific deletion of the vitamin D receptor gene results in cardiac hypertrophy.

Background: A variety of studies carried out using either human subjects or laboratory animals suggest that vitamin D and its analogues possess important beneficial activity in the cardiovascular system. Using Cre-Lox technology we have selectively deleted the vitamin D receptor (VDR) gene in the cardiac myocyte in an effort to better understand the role of vitamin D in regulating myocyte structure and function.

Methods And Results: Targeted deletion of the exon 4 coding sequence in the VDR gene resulted in an increase in myocyte size and left ventricular weight/body weight versus controls both at baseline and following a 7-day infusion of isoproterenol.

A murine model of isolated cardiac steatosis leads to cardiomyopathy.

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 role for the cell cycle phosphatase Cdc25a in vitamin D-dependent inhibition of adult rat vascular smooth muscle cell proliferation.

We have explored the mechanism(s) underlying 1,25 dihydroxyvitamin D's (1,25(OH)(2)D) suppression of agonist-induced vascular smooth muscle cell (VSMC) proliferation. Quiescent cultured adult rat VSMC were treated with 1,25(OH)(2)D for 48h and endothelin (ET) or angiotensin II (AII) for the final 24h. We show that VSMC responded to 1,25(OH)(2)D or its less hypercalcemic analogue RO 25-6760 with ∼70% inhibition of ET-dependent (3)H-thymidine incorporation.

Vitamin D-dependent suppression of endothelin-induced vascular smooth muscle cell proliferation through inhibition of CDK2 activity.

1,25 dihydroxyvitamin D(3) (1,25 (OH)2 D) and its less hypercalcemic analogues have been shown to inhibit the proliferation of vascular smooth muscle cells (VSMC) in culture. However, the mechanism(s) underlying this suppression is not well understood. Here we have shown that 1,25 (OH)2 D and its analogues (RO-25-6760 and RO-23-7553) inhibit endothelin (ET)-dependent DNA synthesis and cell proliferation in neonatal rat aortic VSMC.

Atrial natriuretic peptide suppresses endothelin gene expression and proliferation in cardiac fibroblasts through a GATA4-dependent mechanism.

Aims: Atrial natriuretic peptide (ANP) is a hormone that has both antihypertrophic and antifibrotic properties in the heart. We hypothesized that myocyte-derived ANP inhibits endothelin (ET) gene expression in fibroblasts.

Methods And Results: We have investigated the mechanism(s) involved in the antiproliferative effect of ANP on cardiac fibroblasts in a cell culture model.

Tonicity-dependent induction of Sgk1 expression has a potential role in dehydration-induced natriuresis in rodents.

In various mammalian species, including humans, water restriction leads to an acute increase in urinary sodium excretion. This process, known as dehydration natriuresis, helps prevent further accentuation of hypernatremia and the accompanying rise in extracellular tonicity. Serum- and glucocorticoid-inducible kinase (Sgk1), which is expressed in the renal medulla, is regulated by extracellular tonicity.

Endothelin-stimulated human B-type natriuretic peptide gene expression is mediated by Yin Yang 1 in association with histone deacetylase 2.

Increased B-type natriuretic peptide (BNP) gene expression is regarded as one of the hallmarks of cardiac myocyte hypertrophy. Here we demonstrate that both basal- and endothelin-1-dependent stimulation of human (h) BNP gene transcription requires the presence of an intact Yin Yang 1 (YY1) binding site positioned at -62 bp relative to the transcription start site. Mutation of this site reduced both basal and stimulated hBNP promoter activity.

Expression of the vitamin d receptor is increased in the hypertrophic heart.

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.

A role for p38 mitogen-activated protein kinase and c-myc in endothelin-dependent rat aortic smooth muscle cell proliferation.

We have demonstrated recently that endothelin (ET) stimulates rat aortic smooth muscle cell proliferation through an extracellular signal-regulated kinase (ERK)-dependent mechanism. Approximately 70% of ET-dependent [3H]-thymidine incorporation in these cells signals through this system. In the present study, we show that the residual mitogenic activity requires an intact p38 mitogen-activated protein kinase (p38 MAPK) system and increased c-myc gene expression.

C-type natriuretic Peptide down-regulates expression of its cognate receptor in rat aortic smooth muscle cells.

The C-type natriuretic (CNP) peptide signals through the type B natriuretic peptide receptor (NPR-B) in vascular smooth muscle cells to activate the particulate guanylyl cyclase activity intrinsic to that receptor and raise cellular cyclic GMP levels. In the present study, we demonstrate that CNP down-regulates the expression of this receptor leading to a reduction in NPR-B activity. Pretreatment of rat aortic smooth muscle cells with CNP reduces NPR-B activity, NPR-B protein levels, NPR2 (NPR-B gene) mRNA levels, and NPR2 promoter activity.

1,25-dihydroxyvitamin D inhibits human ANP gene promoter activity.

1,25-dihydroxyvitamin D, through association with its cognate nuclear receptor, has been shown to have important effects in the cardiovascular and renal systems. We have shown previously that the liganded vitamin D receptor (VDR) inhibits hypertrophy and expression of hypertrophy-sensitive genes (i.e.

1,25 dihydroxyvitamin d amplifies type a natriuretic peptide receptor expression and activity in target cells.

1,25 dihydroxyvitamin D (VD) has been shown to exert a number of beneficial effects on cardiovascular function, including reduction in BP and inhibition of cardiac hypertrophy. In an effort to identify a possible mechanistic link between VD and these salutary effects, the role of VD in controlling the activity and expression of the type A natriuretic peptide receptor (NPR-A), a receptor that signals reductions in BP and suppression of cellular growth in the myocardium and vascular wall, was investigated. VD, as well as the nonhypercalcemic analogue RO-25-6760, increased NPR-A-dependent cyclic guanosine monophosphate production and NPR-A gene expression in cultured rat aortic smooth muscle cells.