Our recent studies suggest that 1,25-dihydroxyvitamin D3 functions as an endocrine suppressor of renin biosynthesis. Genetic disruption of the vitamin D receptor (VDR) results in overstimulation of the renin-angiotensin system (RAS), leading to high blood pressure and cardiac hypertrophy. Consistent with the higher heart-to-body weight ratio, the size of left ventricular cardiomyocytes in VDR knockout (KO) mice was markedly increased compared with wild-type (WT) mice. As expected, levels of atrial natriuretic peptide (ANP) mRNA and circulating ANP were also increased in VDRKO mice. Treatment of VDRKO mice with captopril reduced cardiac hypertrophy and normalized ANP expression. To investigate the role of the cardiac RAS in the development of cardiac hypertrophy, the expression of renin, angiotensinogen, and AT-1a receptor in the heart was examined by real-time RT-PCR and immunostaining. In VDRKO mice, the cardiac renin mRNA level was significantly increased, and this increase was further amplified by captopril treatment. Consistently, intense immunostaining was detected in the left ventricle of captopril-treated WT and VDRKO mice by use of an anti-renin antibody. Levels of cardiac angiotensinogen and AT-1a receptor mRNAs were unchanged in the mutant mice. These data suggest that the cardiac hypertrophy seen in VDRKO mice is a consequence of activation of both the systemic and cardiac RAS and support the notion that 1,25-dihydroxyvitamin D(3) regulates cardiac functions, at least in part, through the RAS.

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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. This report summarizes recent research on the roles for vitamin D in cancer, immunity and autoimmune diseases, cardiovascular and respiratory health, pregnancy, obesity, erythropoiesis, diabetes, muscle function, and aging.

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 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. There was no increase in interstitial fibrosis. These knockout mice demonstrated a reduction in end diastolic and end systolic volume by echocardiography, activation of the fetal gene program (i.e. increased atrial natriuretic peptide and alpha skeletal actin gene expression) and increased expression of MCIP 1, a direct downstream target of calcineurin/NFAT signaling. Treatment of neonatal cardiomyocytes with 1,25- dihydroxyvitamin D partially reduced isoproterenol-induced MCIP 1 mRNA and protein levels and MCIP 1 gene promoter activity. Conclusions Collectively, these studies demonstrate that the vitamin D-VDR signaling system possesses direct, anti-hypertrophic activity in the heart. This appears to involve, at least in part, suppression of the pro-hypertrophic calcineurin/NFAT/MCIP 1 pathway. These studies identify a potential mechanism to account for the reported beneficial effects of vitamin D in the cardiovascular system.

Abstract1,25 (OH) 2 Vitamin D 3 (VD 3 ) and retinoic acid (RA) function as ligands for nuclear receptors which regulate transcription. Though the cardiovascular system is not thought to represent a classical target for these ligands, it is clear that both cardiac myocytes and vascular smooth muscle cells respond to these agents with changes in growth characteristics and gene expression. In this study we demonstrate that each of these ligands suppresses many of the phenotypic correlates of endothelin-induced hypertrophy in a cultured neonatal rat cardiac ventriculocyte model. Each of these agents reduced endothelin-stimulated ANP secretion in a dose-dependent fashion and the two in combination proved to be more effective than either agent used alone (VD 3 : 49%; RA: 52%; VD 3 ϩ RA: 80% inhibition). RA, at concentrations known to activate the retinoid X receptor, and, to a lesser extent, VD 3 effected a reduction in atrial natriuretic peptide, brain natriuretic peptide, and ␣ -skeletal actin mRNA levels. Similar inhibition (VD 3 : 30%; RA: 33%; VD 3 ϩ RA: 59% inhibition) was demonstrated when cells transfected with reporter constructs harboring the relevant promoter sequences were treated with VD 3 and/or RA for 48 h. These effects were not accompanied by alterations in endothelin-induced c-fos , c-jun , or c-myc gene expression, suggesting either that the inhibitory locus responsible for the reduction in the mRNA levels lies distal to the activation of the immediate early gene response or that the two are not mechanistically coupled. Both VD 3 and RA also reduced

We have examined the effects of the natriuretic peptides on DNA synthesis in primary cultures of neonatal rat cardiac fibroblasts. Binding analysis using 125I-labeled atrial natriuretic peptide identified a single class of high-affinity binding sites (Kd = 0.03 +/- 0.01 nmol/L) in these cells. Of these sites, 80% appear to be of the natriuretic peptide C receptor subtype, with the remainder being A and B receptor subtypes. Northern blot analysis confirmed the presence of all three natriuretic peptide receptors in these cells. Atrial natriuretic peptide (10(-7) mol/L) effected a modest but consistent reduction in both agonist- and stretch-stimulated [3H]thymidine incorporation (17% to 41%). Moreover, brain natriuretic peptide (10(-7) mol/L), C-type natriuretic peptide (10(-7) mol/L), and des-[Gln18,Ser19,Gly20,Leu21,Gly22]-ANF 4-23-NH2 (10(-7) to 10(-6) mol/L) all proved capable of antagonizing growth factor-dependent [3H]thymidine incorporation (the inhibition ranged from 14% to 28%) and cell proliferation, suggesting that all three natriuretic peptide receptor subtypes are involved in the regulation of mitogenesis in these cultures. The inhibition by atrial natriuretic peptide was amplified by cotreatment with phosphodiesterase inhibitors. Similar reduction in [3H]thymidine incorporation was seen after treatment with 8-bromo-cGMP (10(-4) to 10(-3) mol/L) or nitroprusside (10(-4) to 10(-3) mol/L). These results suggest an important paracrine role for the natriuretic peptides in regulating fibroblast growth during cardiac hypertrophy.

This article reports 8 examples of a rare cyst of the jaws that appears to be a distinct entity and which we have named glandular odontogenic cyst because of its unusual histopathological features. This lesion occurs over a wide age range in both sexes, tends to recur, and may become very large. However, one example in this series remained small over a period of 9 years; another, somewhat atypical example, was associated with an ameloblastoma.

IntroductionSustained hemodynamic overload elicits a series of functional and structural changes in the ventricular myocyte that culminate in cardiac hypertrophy. This is viewed as a compensatory response that, over the short term, results in improved cardiac performance; however, protracted exposure to the hypertrophic stimulus often results in an alteration in phenotype that leads to progressive heart failure. Clinical hypertrophy has, in fact, been linked to increased mortality independent of associated cardiovascular risk factors (1).At the cellular level, hypertrophy is thought to develop in response to a combination of mechanical (i.e., load-dependent) and neurohumoral stimuli, such as angiotensin II (AII), endothelin (ET), and adrenergic agonists. In cultured neonatal rat cardiac myocytes, both mechanical (2-4) and biochemical (5-8) stimuli effect a series of changes in gene expression that closely parallel those seen in the hypertrophied heart in vivo (9). This includes the sequential activation of immediate early genes (e.g., protooncogenes like c-jun, c-fos, and c-myc), a fetal gene program (e.g., atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP], skeletal α-actin, and β-myosin heavy chain) that is typically quiescent in the nonhypertrophied adult ventricular myocardium, and the structural sarcomeric genes that contribute the protein infrastructure associated with hypertrophy (e.g., cardiac α-actin and myosin light chain-2) (9).The signaling cascades underlying the hypertrophic phenotype remain only partially understood. Protein kinase C (10), calcium/calmodulin (11), calcineurin (12-13), nonreceptor protein tyrosine kinases (14, 15), the Janus kinase/STAT system (16, 17), small G proteins (e.g., Ras, Rac, Rho, Cdc42) (18-21), and the various mitogen-activated protein kinases (i.e., ERKs, JNKs, and p38 MAPKs) (22-38) have each been implicated as playing a role in signaling hypertrophy. The MAPKs in particular have been the focus of considerable attention. Hypertrophic stimuli have been shown to activate ERK (22-24), JNK (30, 32), and p38 (34, 37, 38) in either cultured ventricular myocytes or intact myocardial tissue. Whereas interference with the ERK pathway has been shown to block some aspects of hypertrophy-dependent gene expression, it does not affect the morphological changes accompanying hypertrophy (27); in some instances (29) it has been dissociated from the hypertrophic program completely. JNKs have also been linked to hypertrophy (28-32), although recent studies have raised questions about the importance of these kinases in signaling various aspects of the phenotype (37). Activation of p38 by upstream kinases (e.g., MKK6) (35) or hypertrophic agonists (38) has been associated with effects on myocyte growth. Of note, the nature of the effect appears to be isoform specific. Overexpression of activated MKK3 (MKK3bE) elicited both characteristic hypertrophic changes and increased apoptosis in ade- Application of mechanical strain to neonatal rat ventricular myocytes in culture evo...