Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our previous studies showed vitamin D deficiency results in increased cardiac contractility, hypertrophy and fibrosis and has profound effects on heart proteomics, structure and function in rat. In this study we found that the heart in vitamin D receptor knockout (VDR-KO) mice is hypertrophied. Six homozygous VDR knockout (-/-), six wild type (+/+) and six heterozygous (+/-) mice were fed a diet containing 2% Ca, 1.25% P and 20% lactose to maintain normal blood calcium and phosphate levels for 12 months. Tail-cuff blood pressure was performed on all mice. Blood pressure determinations showed no differences in systolic or mean blood pressure in WT (+/+), KO (-/-) or HETERO (+/-) mice at 3 and 6 months. However, decreased systolic BP in the KO mice relative to WT at 9 months of age was observed. ECG analysis showed no significant differences in the intact KO, HETERO or WT mice. The mice were killed at 12 months. Heart weight/body weight ratio was 41% (P<.003) greater in the KO mice versus WT and HETERO was 19% (P<.05) increased versus WT. Other VDR-KO tissues did not display hypertrophy. Cross sectional and longitudinal analysis of the heart myofibrils showed highly significant cellular hypertrophy in VDR-KO mice. Trichrome staining of heart tissue showed marked increase in fibrotic lesions in the KO mice. Analysis of plasma renin activity, angiotensin II (AII) and aldosterone levels showed elevated but not significantly different renin activity in KO versus WT and no significant differences in AII or aldosterone levels. Our data do not support the concept that the renin-angiotensin system or hypertension are the factors that elicit these changes. Data presented here reveal that ablation of the VDR signaling system results in profound changes in heart structure. We propose that calcitriol acts directly on the heart as a tranquilizer by blunting cardiomyocyte hypertrophy.
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PMID:Characterization of heart size and blood pressure in the vitamin D receptor knockout mouse. 1727 89

Hydroxylation of 25(OH)D to 1,25-dihydroxyvitamin D and signaling through the vitamin D receptor occur in various tissues not traditionally involved in calcium homeostasis. Laboratory studies indicate that 1,25-dihydroxyvitamin D suppresses renin expression and vascular smooth muscle cell proliferation; clinical studies demonstrate an inverse association between ultraviolet radiation, a surrogate marker for vitamin D synthesis, and blood pressure. We prospectively studied the independent association between measured plasma 25-hydroxyvitamin D [25(OH)D] levels and risk of incident hypertension and also the association between predicted plasma 25(OH)D levels and risk of incident hypertension. Two prospective cohort studies including 613 men from the Health Professionals' Follow-Up Study and 1198 women from the Nurses' Health Study with measured 25(OH)D levels were followed for 4 to 8 years. In addition, 2 prospective cohort studies including 38 388 men and 77 531 women with predicted 25(OH)D levels were followed for 16 to 18 years. During 4 years of follow-up, the multivariable relative risk of incident hypertension among men whose measured plasma 25(OH)D levels were <15 ng/mL (ie, vitamin D deficiency) compared with those whose levels were >or=30 ng/mL was 6.13 (95% confidence interval [CI]: 1.00 to 37.8). Among women, the same comparison yielded a relative risk of 2.67 (95% CI: 1.05 to 6.79). The pooled relative risk combining men and women with measured 25(OH)D levels using the random-effects model was 3.18 (95% CI: 1.39 to 7.29). Using predicted 25(OH)D levels in the larger cohorts, the multivariable relative risks comparing the lowest to highest deciles were 2.31 (95% CI: 2.03 to 2.63) in men and 1.57 (95% CI: 1.44 to 1.72) in women. Plasma 25(OH)D levels are inversely associated with risk of incident hypertension.
Hypertension 2007 May
PMID:Plasma 25-hydroxyvitamin D levels and risk of incident hypertension. 1836 26

The 'classical' effects of vitamin D receptor activator or agonist (VDRA) therapy for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease primarily involves suppressive effects on the parathyroid gland, and regulation of calcium and phosphorus absorption in the intestine and mobilisation in bone. Observational studies in haemodialysis patients report improved cardiovascular and all-cause survival among those receiving VDRA therapy compared with those not on VDRA therapy. Among VDRAs, the selective VDRA paricalcitol has been associated with greater survival than nonselective VDRAs, such as calcitriol (1,25-dihydroxyvitamin D(3)). The survival benefits of paricalcitol appear to be linked, at least in part, to 'nonclassical' actions of VDRAs, possibly through VDRA-mediated modulation of gene expression. In cardiovascular tissues, VDRAs are reported to have beneficial effects such as anti-inflammatory and antithrombotic effects, inhibition of vascular smooth muscle cell proliferation, inhibition of vascular calcification and stiffening, and regression of left ventricular hypertrophy. VDRAs are also reported to negatively regulate the renin-angiotensin system, which plays a key role in hypertension, myocardial infarction and stroke. The selective VDRAs, paricalcitol and maxacalcitol, are associated with direct protective effects on glomerular architecture and antiproteinuric effects in response to renal damage. Paricalcitol regulates several cardiovascular and renal parameters more favourably than nonselective VDRAs. Complex nonclassical effects, which are not clearly understood, possibly contribute to the improved survival seen with VDRAs, especially paricalcitol.
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PMID:Nonclassical aspects of differential vitamin D receptor activation: implications for survival in patients with chronic kidney disease. 1788 84

Endothelial cells detect physical and chemical changes in the blood vessels, and release various factors to counter these changes to maintain homeostasis. Traditional cardiovascular disease risk factors, such as hypertension, dyslipidemia and diabetes, cause endothelial dysfunction characterized by off-balanced vasodilation/vasoconstriction, increased oxidative stress and inflammation, deregulation of thrombosis and fibrinolysis, abnormal smooth muscle cell proliferation, and a deficient repair mechanism. Patients with chronic kidney disease (CKD) have a much higher risk of cardiovascular disease and mortality than the general population. Endothelial dysfunction is commonly observed in CKD, likely preceding other cardiovascular complications. Lipid-lowering agents, such as statins, improve endothelial functions and are effective in reducing cardiovascular disease risk in the general population, but have not demonstrated comparable efficacy in the CKD patient population. Similarly, antidiabetic agents, such as thiazolidinediones, that improve endothelial function in the general population are less efficacious than expected in slowing disease progression and reducing cardiovascular disease risk in CKD patients. Interestingly, agents that activate the vitamin D receptor (VDR) for the treatment of hyperparathyroidism secondary to CKD are associated with a survival benefit in CKD patients that is likely mediated through the effects of the VDR on modulating key components involved in endothelial dysfunction. However, a randomized, clinical study is required to confirm the survival benefit of VDR activation therapy for CKD patients. Results from clinical studies suggest that managing hypertension alone may not be adequate in slowing CKD progression and its related cardiovascular complications. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers that target the renin-angiotensin system slow CKD progression, possibly due to their effects on improving endothelial function, independent of controlling blood pressure.
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PMID:Endothelial dysfunction and chronic kidney disease: treatment options. 1872 4

The renal renin-angiotensin system plays a major role in determining the rate of chronic renal disease progression. Treatment with activators of the vitamin D receptor retards the progression of experimental chronic renal disease, and vitamin D is known to suppress the renin-angiotensin system in other organs. Here we determined if the beneficial effects of paricalcitol (19-nor 1,25-dihydroxyvitamin D(2)) were associated with suppression of renin-angiotensin gene expression in the kidney. Rats with the remnant kidney model of chronic renal failure (5/6 nephrectomy) were given two different doses of paricalcitol thrice weekly for 8 weeks. Paricalcitol was found to decrease angiotensinogen, renin, renin receptor, and vascular endothelial growth factor mRNA levels in the remnant kidney by 30-50 percent compared to untreated animals. Similarly, the protein expression of renin, renin receptor, the angiotensin type 1 receptor, and vascular endothelial growth factor were all significantly decreased. Glomerular and tubulointerstitial damage, hypertension, proteinuria, and the deterioration of renal function resulting from renal ablation were all similarly and significantly improved with both treatment doses. These studies suggest that the beneficial effects of vitamin D receptor activators in experimental chronic renal failure are due, at least in part, to down-regulation of the renal renin-angiotensin system.
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PMID:Suppression of renin-angiotensin gene expression in the kidney by paricalcitol. 1914 59

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-alpha-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.
Hypertension 2008 Dec
PMID:Expression of the vitamin d receptor is increased in the hypertrophic heart. 1893 43

Lead (Pb) induces arterial hypertension in consequence of low exposures, which is not manifested by Pb toxic effects on the marrow, kidneys or other organs. Pb hypertensive effect, in the range of blood concentration from 10 to 40 microg/dl, has been evidenced by numerous experimental and population studies. However, the presence of significant correlation between blood lead level and systolic and/or diastolic blood pressure is not confirmed by some epidemiological studies. These discrepancies can be explained by the observation, that Pb-induced hypertension results rather from past than from current exposure, hence the arterial pressure values should be rather related to bone than to blood lead level. The occurrence of polymorphism of genes involved in Pb toxic effect may be another explanation. The interaction between Pb toxicity and ALAD gene polymorphisms on hematopoesis is observed in workers occupationally exposed to lead. These polymorphisms, occurring in a single form or in connection with other polymorphisms, seem to be implicated in Pb-induced hypertension, e.g., vitamin D receptor gene. The results of experimental studies show that the correlation between Pb exposure, arterial blood pressure and the presence of polymorphisms of angiotensin converting enzyme and beta(2)adrenergic receptor genes should be analysed in populations. It is likely that studies of other genes polymorphisms, genegene interactions and the interaction between genes and--environmental factors lead to the identification of causes of so called spontaneous hypertension.
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PMID:[Genetic aspects of hypertensive effect of lead]. 1914 24

Continuously emerging evidence indicates that defi ciencies in 25-hydroxyvitamin D and consequently vitamin D receptor (VDR) activation play crucial roles in adversely affecting cardiovascular (CV) health in the general population and those at high risk of CV disease, as well as in patients with chronic kidney disease (CKD). In CKD patients, a lack of VDR activation is one of the main pathophysiological factors contributing to secondary hyperparathyroidism (SHPT). However, this lack of VDR activation has numerous additional implications on CV and renal function, with SHPT being only one symptom of a much more extensive disorder. VDRs are widely expressed throughout the body with manifold activities that involve feedback loops within the CV, immune, and renal systems. Modulation of VDR activator levels results in correlative regulatory effects on mineral homeostasis, hypertension, vascular disease, and vascular calcifi cation, as well as a number of other endpoints in cardiac and renal pathology. Among compounds available for the treatment of SHPT, paricalcitol is a selective VDR activator. The term 'selective' refers to paricalcitol being more selective in affecting VDR pathways in the PTH gland compared with bone and intestine. As such, paricalcitol's selectivity allows for a wider therapeutic window with effects beyond PTH control and mineral management, and may explain, in part, the increased survival advantage with paricalcitol treatment.
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PMID:Importance of vitamin D receptor activation in clinical practice. 1949 16

Vitamin D is an important prohormone for optimal intestinal calcium absorption for mineralization of bone. Because the vitamin D receptor is present in multiple tissues, there has been interest in evaluating other potential functions of vitamin D, particularly, in cardiovascular diseases (CVD). Cross-sectional studies have reported that vitamin D deficiency is associated with increased risk of CVD, including hypertension, heart failure, and ischemic heart disease. Initial prospective studies have also demonstrated that vitamin D deficiency increases the risk of developing incident hypertension or sudden cardiac death in individuals with preexisting CVD. Very few prospective clinical studies have been conducted to examine the effect of vitamin D supplementation on cardiovascular outcomes. The mechanism for how vitamin D may improve CVD outcomes remains obscure; however, potential hypotheses include the downregulation of the renin-angiotensin-aldosterone system, direct effects on the heart, and vasculature or improvement of glycemic control. This review will examine the epidemiologic and clinical evidence for vitamin D deficiency as a cardiovascular risk factor and explore potential mechanisms for the cardioprotective effect of vitamin D.
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PMID:Vitamin D deficiency and risk for cardiovascular disease. 1959 2

Exposure of the skin to sunlight is now considered the most important source of vitamin D in Western countries. It is presumed to contribute approximately two thirds of the total requirement, leaving the remaining one third to the few foods naturally rich in this vitamin. In the skin, vitamin D is synthesized as a cholesterol chain which undergoes structural modifications following exposure to UVB rays. Once produced in the skin or absorbed in the gut as cholecalciferol, vitamin D enters the blood to be transported by a specific vitamin D binding protein, which is synthesized in the liver and has a powerful buffering capacity. The transport system carries the metabolites to the sites of further activation (25-hydroxylation in the liver and 1alpha-hydroxylation in the kidney), ultimately resulting in the production of calcitriol. This last compound, now regarded as a hormone, circulates freely in minimal amounts and, compared with the other metabolites, shows the highest affinity for the vitamin D receptor (VDR). The mechanism of VDR activation is rather complex, resulting in either stimulation or inhibition of protein synthesis. Importantly, besides its presence in parathyroid, bone, kidney and intestine, this receptor has been demonstrated in several tissues, where its stimulation results in a reduced proliferation rate and increased differentiation. Accordingly, vitamin D is now regarded as a complex hormonal system, involved not only in the regulation of divalent ions and bone, but also in the proliferation and differentiation of numerous cell types with potential involvement in several diseases like cancer, immune diseases, diabetes, hypertension and heart failure.
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PMID:[Understanding the different functions of vitamin D]. 1964 19


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