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Post-operative atrial fibrillation (POAF) is a persistent and serious surgical complication that occur in 20-55% of cardiac surgery cases. POAF may lead to adverse health outcomes such as stroke, thromboembolism, cardiac arrest, and mortality, and may develop long-term. Patients have a 2-fold increase in mortality risk and spend about 3.7 more days in the hospital and $16,000 more in medical costs during their visit. The mechanisms and risk factors of POAF are still poorly understood, yet a strong foundation of how a disease process occurs is needed to provide the most effective treatment. Current mechanisms that are postulated to contribute to POAF include an increase in sympathetic tone, oxidative stress, local and systemic inflammation, a trigger that induces atrial substrate changes, a driver to sustain POAF, and electrolyte disturbances such as hypomagnesemia. While needing more research, current risk factors include age, male sex, history of myocardial infarction or heart failure, hypertension, diabetes, obesity, and COPD. Treatments mostly include prophylaxis of repurposed drugs such as beta-blockers, statins, oral anticoagulants, antiarrhythmics, and Vitamin D and electrolyte supplementation. Autonomic denervation has also been a promising preventative measure for patients undergoing cardiac surgery. This critical review article provides an up-to-date and comprehensive summary of the pathophysiology of POAF, current clinical risk factors and management for POAF and discusses new pathways for further investigation.
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Chronic joint inflammation due to increased secretion of pro-inflammatory cytokines, the accumulation of inflammatory immune cells (mainly macrophages), and vitamin D deficiency leads to cartilage degeneration and the development of osteoarthritis (OA). This study investigated the effect of vitamin D status on the expression of mediators of inflammation including interleukin (IL)-33, IL-37, IL-6, tumor necrosis factor (TNF)-α, toll-like receptors (TLRs), damage-associated molecular patterns (DAMPs), and matrix metalloproteinases (MMPs) in degenerating the cartilage of hyperlipidemic microswine. Additionally, in vitro studies with normal human chondrocytes were conducted to investigate the effect of calcitriol on the expression of IL-33, IL-37, IL-6, TNF-α, TLRs, DAMPs, and MMPs. We also studied the effects of calcitriol on macrophage polarization using THP-1 cells. The results of this study revealed that vitamin D deficiency is associated with an increased expression of IL-33, IL-37, IL-6, TNF-α, TLRs, DAMPs, and MMPs, while vitamin D supplementation is associated with a decreased expression of the former. Additionally, vitamin D deficiency is associated with increased M1, while vitamin D-supplemented microswine cartilage showed increased M2 macrophages. It was also revealed that calcitriol favors M2 macrophage polarization. Taken together, the results of this study suggest that modulating expression of IL-33, IL-6, TNF-α, TLRs, DAMPs, and MMPs with vitamin D supplementation may serve as a novel therapeutic to attenuate inflammation and cartilage degeneration in osteoarthritis.
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Inflammation is a major contributor to the development and progression of atherosclerosis. Interleukin (IL)-33 and IL-37, members of the IL-1 family, modulate inflammation, with IL-33 having a pro-inflammatory effect and IL-37 having anti-inflammatory properties. IL-37 is constitutively expressed at low levels but upregulated in inflammatory contexts. The aim of this study was to evaluate the effect of vitamin D on the expression of IL-33, IL-37, macrophages, and caspase-1 in the neointimal tissue of coronary artery in Yucatan microswine with vitamin D deficient, sufficient, and supplemented status. The intimal injury was induced by balloon angioplasty and stenting in the coronary artery, and tissues were harvested after 6 months. The expression of various proteins of interest was evaluated by immunostaining. Increased expression of IL-33 and IL-37 in the neointimal tissue of the vitamin D deficient, as compared to the sufficient and supplemented microswine, as revealed by histological evaluation and semi-quantitative analysis, suggested the immunomodulatory effect of vitamin D on the expression of IL-33 and IL-37. The minimal expression or absence of IL-33 and IL-37 expression in stented arteries is suggestive of an attenuated inflammatory response in stented arteries, compared to balloon angioplasty. The decreased IL-33 expression in the sufficient and supplemented microswine could be a potential mechanism for controlling the inflammatory process and neointima formation leading to attenuated luminal narrowing of the coronary artery. Overall, these results support supplementation of vitamin D to attenuate inflammation, neointima formation, and restenosis.
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Angioplastia Coronária com Balão/métodos , Doença da Artéria Coronariana/imunologia , Hiperlipidemias/fisiopatologia , Interleucina-1/metabolismo , Interleucina-33/metabolismo , Neointima/imunologia , Stents , Vitamina D/metabolismo , Animais , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/terapia , Suplementos Nutricionais , Imunomodulação , Neointima/patologia , Neointima/terapia , SuínosRESUMO
Intracoronary stenting is a common procedure in patients with coronary artery disease (CAD). Stent deployment stretches and denudes the endothelial layer, promoting a local inflammatory response, resulting in neointimal hyperplasia. Vitamin D deficiency associates with CAD. In this study, we examined the association of vitamin D status with high mobility group box 1 (HMGB1)-mediated pathways (HMGB1, receptor for advanced glycation end products [RAGE], and Toll-like receptor-2 and -4 [TLR2 and TLR4]) in neointimal hyperplasia in atherosclerotic swine following bare metal stenting. Yucatan microswine fed with a high-cholesterol diet were stratified to receive vitamin D-deficient (VD-DEF), vitamin D-sufficient (VD-SUF), and vitamin D-supplemented (VD-SUP) diet. After 6 months, PTCA (percutaneous transluminal balloon angioplasty) followed by bare metal stent implantation was performed in the left anterior descending (LAD) artery of each swine. Four months following coronary intervention, angiogram and optical coherence tomography (OCT) were performed and swine euthanized. Histology and immunohistochemistry were performed in excised LAD to evaluate the expression of HMGB1, RAGE, TLR2, and TLR4. OCT analysis revealed the greatest in-stent restenosis area in the LAD of VD-DEF compared to VD-SUF or VD-SUP swine. The protein expression of HMGB1, RAGE, TLR2, and TLR4 was significantly higher in the LAD of VD-DEF compared to VD-SUF or VD-SUP swine. Vitamin D deficiency was associated with both increased in-stent restenosis and increased HMGB1-mediated inflammation noted in coronary arteries following intravascular stenting. Inversely, vitamin D supplementation was associated with both a decrease in this inflammatory profile and in neointimal hyperplasia, warranting further investigation for vitamin D as a potential adjunct therapy following coronary intervention.
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Doença da Artéria Coronariana/cirurgia , Proteína HMGB1/metabolismo , Hiperplasia/prevenção & controle , Neointima/prevenção & controle , Intervenção Coronária Percutânea/efeitos adversos , Stents/efeitos adversos , Vitamina D/administração & dosagem , Animais , Doença da Artéria Coronariana/patologia , Feminino , Proteína HMGB1/genética , Hiperplasia/etiologia , Hiperplasia/metabolismo , Hiperplasia/patologia , Masculino , Neointima/etiologia , Neointima/metabolismo , Neointima/patologia , Suínos , Vitaminas/administração & dosagemRESUMO
Vitamin D functions as a potent immunomodulator by interacting with many immune cells however, its role in regulating inflammation in the epicardial adipose tissue (EAT) is unclear. In the EAT of atherosclerotic microswine that were fed with deficient, sufficient or supplemented levels of vitamin D, we evaluated the phenotype of the macrophages. Vitamin D treatment was continued for 12 months and serum 25(OH)D levels were measured regularly. Infiltration of M1/M2 macrophage was investigated by immunostaining for CCR7 and CD206, respectively in conjunction with a pan macrophage marker CD14. Significant difference in the number of CCR7+ cells was observed in the EAT from vitamin D-deficient swine compared to vitamin D-sufficient or -supplemented swine. Expression of CD206 correlated with high levels of serum 25(OH)D indicating a significant increase in M2 macrophages in the EAT of vitamin D-supplemented compared to -deficient swine. These findings suggest that vitamin D-deficiency exacerbates inflammation by increasing pro-inflammatory M1 macrophages, while vitamin D-supplementation attenuates the inflammatory cytokines and promotes M2 macrophages in EAT. This study demonstrates the significance of vitamin D mediated inhibition of macrophage mediated inflammation in the EAT during coronary intervention in addition to its immunomodulatory role. However, additional studies are required to identify the cellular mechanisms that transduce signals between macrophages and smooth muscle cells during restenosis in the presence and absence of vitamin D.
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Tecido Adiposo/metabolismo , Aterosclerose/metabolismo , Macrófagos/metabolismo , Pericárdio/metabolismo , Vitamina D/sangue , Animais , Doença da Artéria Coronariana/genética , Reestenose Coronária , Suplementos Nutricionais , Feminino , Inflamação , Fenótipo , Receptores de Calcitriol/genética , Suínos , Deficiência de Vitamina D/sangue , Vitaminas/sangueRESUMO
The role of vitamin D beyond its classical function in calcium homeostasis has been of significant interest in recent years. There has been expanding research on the pleiotropic role of vitamin D in pregnancy and the implications of its deficiency on maternal-fetal outcomes. Several studies have associated low maternal vitamin D status to adverse outcomes in pregnancy, including preeclampsia, gestational diabetes, preterm births, low birth weight, and others. Several randomized controlled clinical trials of Vitamin D supplementation during pregnancy have also been conducted. Though some of the studies found improvement in pregnancy outcomes with vitamin D supplementation, others have not shown any association. In this article, we have critically reviewed the observational and interventional studies, published primarily within the past two years (January 2014 to February 2016) on the influence of vitamin D deficiency on pregnancy and the impact of its supplementation. The potential underlying mechanisms of vitamin D in regulating each of the outcomes have also been discussed.
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Suplementos Nutricionais , Complicações na Gravidez/etiologia , Resultado da Gravidez , Deficiência de Vitamina D/complicações , Vitamina D/uso terapêutico , Feminino , Humanos , Recém-Nascido , Estudos Observacionais como Assunto , Gravidez , Complicações na Gravidez/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina D/prevenção & controleRESUMO
Inflammation is associated with glenohumeral arthritis and rotator cuff tendon tears. Epigenetically, miRNAs tightly regulate various genes involved in the inflammatory response. Alterations in the expression profile of miRNAs and the elucidation of their target genes with respect to the pathophysiology could improve the understanding of their regulatory role and therapeutic potential. Here, we screened key miRNAs that mediate inflammation and linked with JAK2/STAT3 pathway with respect to the coincidence of glenohumeral arthritis in patients suffering from rotator cuff injury (RCI). Human resected long head of the biceps tendons were examined for miRNA profile from two groups of patients: Group 1 included the patients with glenohumeral arthritis and massive rotator cuff tears and the Group 2 patients did not have arthritis or rotator cuff tears. The miRNA profiling revealed that 235 miRNAs were highly altered (fold change less than -3 and greater than +2 were considered). Data from the NetworkAnalyst program revealed the involvement and interaction between 3,430 different genes associated with inflammation out of which 284 genes were associated with JAK2/STAT3 pathway and interconnect 120 different pathways of inflammation. Around 1,500 miRNAs were found to play regulatory role associated with these genes of inflammatory responses and 77 miRNAs were found to regulate more than 10 genes. Among them, 25 genes with less than tenfold change were taken to consideration which altogether constitute for the regulation of 102 genes. Targeting these miRNAs and the underlying regulatory mechanisms may advance our knowledge to develop promising therapies in the management of shoulder tendon pathology.
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Artrite/metabolismo , Tendinopatia do Cotovelo/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , MicroRNAs/biossíntese , Articulação do Ombro/metabolismo , Artrite/patologia , Tendinopatia do Cotovelo/patologia , Feminino , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Articulação do Ombro/patologiaRESUMO
Vitamin D is critical in mineral homeostasis and skeletal health and plays a regulatory role in nonskeletal tissues. Vitamin D deficiency is associated with chronic inflammatory diseases, including diabetes and obesity, both strong risk factors for cardiovascular diseases (CVDs). CVDs, including coronary artery disease, myocardial infarction, hypertrophy, cardiomyopathy, cardiac fibrosis, heart failure, aneurysm, peripheral arterial disease, hypertension, and atherosclerosis, are major causes of morbidity and mortality. The association of these diseases with vitamin D deficiency and improvement with vitamin D supplementation suggest its therapeutic benefit. The authors review the findings on the association of vitamin D deficiency and CVDs.
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Doenças Cardiovasculares/etiologia , Deficiência de Vitamina D/complicações , Vitamina D/uso terapêutico , Doenças Cardiovasculares/sangue , Citocinas/sangue , Humanos , Vitamina D/sangue , Deficiência de Vitamina D/sangueRESUMO
BACKGROUND: Osteoarthritis (OA) currently affects 10% of the American population. There has been a recent push to determine exactly what causes OA and how it can be treated most effectively. Serum vitamin D levels have been associated with OA and may have an effect on articular cartilage remodeling. PURPOSE: To critically review the published research on the effect of vitamin D on articular cartilage and the development of OA as well as on the mechanism behind cartilage regeneration and degeneration. STUDY DESIGN: Review. METHODS: A systematic search of PubMed and the Web of Science was performed for relevant studies published in the English language through April 30, 2016, using the terms vitamin D, articular cartilage, and osteoarthritis. RESULTS: On a molecular level, 1α,25(OH)2D3, the activated form of vitamin D, plays a role in articular cartilage degeneration. Vitamin D binds to vitamin D receptors, triggering a signaling cascade that leads to chondrocyte hypertrophy. In clinical trials, vitamin D deficiency poses a risk factor for OA, and those with decreased cartilage thickness are more likely to be vitamin D-insufficient. CONCLUSION: The role of vitamin D supplementation in the treatment or prevention of OA remains uncertain. More research is needed to reconcile these conflicting findings.
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PURPOSE: Vitamin D is a potent immunomodulator capable of dampening inflammatory signals in several cell types involved in the asthmatic response. Its deficiency has been associated with increased inflammation, exacerbations, and overall poor outcomes in patients with asthma. Given the increase in the prevalence of asthma over the past few decades, there has been enormous interest in the use of vitamin D supplementation as a potential therapeutic option. Here, we critically reviewed the most recent findings from in vitro studies, animal models, and clinical trials regarding the role of vitamin D in treating bronchial asthma. METHODS: Using the key terms [Vitamin D, asthma, clinical trials, in vivo and in vitro studies], the [PubMed, Google Scholar] databases were searched for [clinical trials, original research articles, meta-analyses, and reviews], English-language articles published from [2012] to the present. Articles that were [Articles that did not meet these criteria were excluded] excluded from the analysis. FINDINGS: Several studies have found that low serum levels of vitamin D (< 20 ng/mL) are associated with increased exacerbations, increased airway inflammation, decreased lung function, and poor prognosis in asthmatic patients. Results from in vitro and in vivo studies in animals and humans have suggested that supplementation with vitamin D may ameliorate several hallmark features of asthma. However, the findings obtained from clinical trials are controversial and do not unequivocally support a beneficial role of vitamin D in asthma. Largely, interventional studies in children, pregnant women, and adults have primarily found little to no effect of vitamin D supplementation on improved asthma symptoms, onset, or progression of the disease. This could be related to the severity of the disease process and other confounding factors. IMPLICATIONS: Despite the conflicting data obtained from clinical trials, vitamin D deficiency may influence the inflammatory response in the airways. Further studies are needed to determine the exact mechanisms by which vitamin D supplementation may induce antiinflammatory effects.
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Asma , Vitamina D , Vitaminas , Animais , Asma/sangue , Asma/tratamento farmacológico , Suplementos Nutricionais , Humanos , Vitamina D/sangue , Vitamina D/farmacologia , Vitamina D/uso terapêutico , Vitaminas/sangue , Vitaminas/farmacologia , Vitaminas/uso terapêuticoRESUMO
The extracellular matrix (ECM) provides core support which is essential for the cell and tissue architectural development. The role of ECM in many pathological conditions has been well established and ECM-related abnormalities leading to serious consequences have been identified. Though much has been explored in regards to the role of ECM in soft tissue associated pathologies, very little is known about its role in inflammatory disorders in tendon. In this study, we performed microRNA (miRNA) expression analysis in the long head of the human shoulder biceps tendon to identify key genes whose expression was altered during inflammation in patients with glenohumeral arthritis. We identified differential regulation of matrix metalloproteinases (MMPs) that could be critical in collagen type replacement during tendinopathy. The miRNA profiling showed consistent results between the groups and revealed significant changes in the expression of seven different miRNAs in the inflamed tendons. Interestingly, all of these seven miRNAs were previously reported to have either a direct or indirect role in regulating the ECM organization in other pathological disorders. In addition, these miRNAs were also found to alter the expression levels of MMPs, which are the key matrix degrading enzymes associated with ECM-related abnormalities and pathologies. To our knowledge, this is the first report which identifies specific miRNAs associated with inflammation and the matrix reorganization in the tendons. Furthermore, the findings also support the potential role of these miRNAs in altering the collagen type ratio in the tendons during inflammation which is accompanied with differential expression of MMPs.
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Artrite/genética , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Matriz Extracelular , MicroRNAs/genética , Articulação do Ombro/patologia , Tendinopatia/genética , Artrite/metabolismo , Artrite/patologia , Estudos de Casos e Controles , Colágeno/metabolismo , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Perfilação da Expressão Gênica , Estudos de Associação Genética , Humanos , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Análise em Microsséries , Ombro , Articulação do Ombro/metabolismo , Tendinopatia/metabolismo , Tendinopatia/patologia , TendõesRESUMO
BACKGROUND: Osteoarthritis (OA) of the knee joint is a degenerative process resulting in cartilage loss. Recent evidence suggests that OA is not merely a disease of cartilage but a disease of the entire knee joint and that inflammation may play an important role. OA has been associated with vitamin D deficiency. Vitamin D as an immunomodulator and anti-inflammatory agent may attenuate inflammation in the knee. The aim of this study was to assess the anti-inflammatory effect of vitamin D on inflammation in the knee. METHODS: This study was conducted with 13 microswine on a high cholesterol diet categorized into three groups of vitamin D-deficient, vitamin D-sufficient, and vitamin D supplementation. After 1 year, microswine were killed, and their knee joint tissues were harvested. Histological and immunofluorescence studies were carried out on the tissue specimens to evaluate the effect of vitamin D status. RESULTS: Histological and immunofluorescence studies of the knee joint tissues showed (1) increased inflammation in the knee joint tissues, (2) fatty infiltration in quadriceps muscle, patellar tendon, and collateral ligaments, and (3) chondrocyte clustering in the vitamin D-deficient and vitamin D-sufficient groups compared with the vitamin D supplementation group. Architectural distortion of the quadriceps muscle, patellar tendon, and collateral ligaments was also seen in the areas of inflammatory foci and fatty infiltration in the vitamin D-deficient group. CONCLUSIONS: Decreased inflammation and fatty infiltration in the vitamin D supplementation group suggest the potential role of vitamin D in attenuating inflammation and fatty infiltration as well as in protecting the architecture of the tissue in the knee joint.
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Anti-Inflamatórios/farmacologia , Cartilagem Articular/patologia , Inflamação/patologia , Articulação do Joelho/efeitos dos fármacos , Osteoartrite do Joelho/patologia , Vitamina D/farmacologia , Tecido Adiposo/patologia , Animais , Cartilagem Articular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Imunofluorescência , Hiperlipidemias , Articulação do Joelho/patologia , Músculo Quadríceps/patologia , SuínosRESUMO
Vitamin D deficiency in human subjects is associated with hypertension, metabolic syndrome and related risk factors of cardiovascular diseases. Serum 25-hydroxyvitamin D levels correlate inversely with adiposity in obese and lean individuals. Bioactive vitamin D, or calcitriol, exerts anti-inflammatory effects on adipocytes, preadipocytes and macrophages in vitro. We tested the hypothesis that vitamin D deficiency alters the phenotype of perivascular adipose tissue (PVAT) leading to impaired function in resistance artery. To examine the effects of vitamin D and PVAT on vascular reactivity, myograph experiments were performed on arteries, with or without intact PVAT, from mice maintained on vitamin D-deficient, vitamin D-sufficient or vitamin D-supplemented diet. Systolic blood pressure was significantly increased in mice on vitamin D-deficient diet. Importantly, vitamin D deficiency enhanced angiotensin II-induced vasoconstriction and impaired the normal ability of PVAT to suppress contractile responses of the underlying mesenteric resistance artery to angiotensin II and serotonin. Furthermore, vitamin D deficiency caused upregulation of the mRNA expression of tumor necrosis factor-α, hypoxia-inducible factor-1α and its downstream target lysyl oxidase in mesenteric PVAT. Incubation of mesenteric arteries under hypoxic conditions impaired the anti-contractile effects of intact PVAT on those arteries from mice on vitamin D-sufficient diet. Vitamin D supplementation protected arteries against hypoxia-induced impairment of PVAT function. The protective effects of vitamin D against vascular dysfunction, hypertension and cardiovascular diseases may be mediated, at least in part, through regulation of inflammatory and hypoxia signaling pathways in PVAT.
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Tecido Adiposo/metabolismo , Artérias/fisiologia , Hipóxia/metabolismo , Inflamação/metabolismo , Resistência Vascular , Vitamina D/metabolismo , Ração Animal , Animais , Pressão Sanguínea , Feminino , Perfilação da Expressão Gênica , Masculino , Artérias Mesentéricas/fisiologia , Camundongos , Contração Muscular , Fenótipo , Vitamina D/administração & dosagemRESUMO
OBJECTIVE: The role of vitamin D deficiency in coronary artery disease (CAD) progression is uncertain. Chronic inflammation in epicardial adipose tissue (EAT) has been implicated in the pathogenesis of CAD. However, the molecular mechanism underlying vitamin D deficiency-enhanced inflammation in the EAT of diseased coronary arteries remains unknown. We examined a mechanistic link between 1,25-dihydroxyvitamin D-mediated suppression of nuclear factor-κB (NF-κB) transporter, karyopherin α4 (KPNA4) expression and NF-κB activation in preadipocytes. Furthermore, we determined whether vitamin D deficiency accelerates CAD progression by increasing KPNA4 and nuclear NF-κB levels in EAT. APPROACH AND RESULTS: Nuclear protein levels were detected by immunofluorescence and Western blot. Exogenous KPNA4 was transported into cells by a transfection approach and constituted lentiviral vector. Swine were administered vitamin D-deficient or vitamin D-sufficient hypercholesterolemic diet. After 1 year, the histopathology of coronary arteries and nuclear protein expression of EAT were assessed. 1,25-dihydroxyvitamin D inhibited NF-κB activation and reduced KPNA4 levels through increased vitamin D receptor expression. Exogenous KPNA4 rescued 1,25-dihydroxyvitamin D-dependent suppression of NF-κB nuclear translocation and activation. Vitamin D deficiency caused extensive CAD progression and advanced atherosclerotic plaques, which are linked to increased KPNA4 and nuclear NF-κB levels in the EAT. CONCLUSIONS: 1,25-dihydroxyvitamin D attenuates NF-κB activation by targeting KPNA4. Vitamin D deficiency accelerates CAD progression at least, in part, through enhanced chronic inflammation of EAT by upregulation of KPNA4, which enhances NF-κB activation. These novel findings provide mechanistic evidence that vitamin D supplementation could be beneficial for the prevention and treatment of CAD.
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Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Doença da Artéria Coronariana/etiologia , Deficiência de Vitamina D/complicações , Transporte Ativo do Núcleo Celular , Adipócitos/efeitos dos fármacos , Adipócitos/patologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Células Cultivadas , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/prevenção & controle , Modelos Animais de Doenças , Progressão da Doença , Hipercolesterolemia/complicações , Interferência de RNA , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Suínos , Porco Miniatura , Fatores de Tempo , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Transfecção , Vitamina D/análogos & derivados , Vitamina D/farmacologia , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina D/metabolismo , Deficiência de Vitamina D/patologia , alfa Carioferinas/genética , alfa Carioferinas/metabolismoRESUMO
Vitamin D is a fat-soluble steroid hormone that activates vitamin D receptor to regulate multiple downstream signaling pathways and transcription of various target genes. There is an association between vitamin D deficiency and increased risk for cardiovascular disease. However, most of the studies are observational and associative in nature with limited data on clinical application. Thus, there is a need for more prospective randomized controlled studies to determine whether or not vitamin D supplementation provides cardiovascular protection. In this study, we examined the effects of the deficiency and supplementation of vitamin D on coronary restenosis following coronary intervention in atherosclerotic Yucatan microswine. Twelve Yucatan microswine were fed vitamin D-deficient (n = 4) or -sufficient (n = 8) high cholesterol diet for 6-months followed by coronary intervention. Post-intervention, swine in the vitamin D-sufficient high cholesterol diet group received daily oral supplementation of either 1,000 IU (n = 4) or 3,000 IU (n = 4) vitamin D3. Six months later, optical coherence tomography (OCT) was performed to monitor the development of intimal hyperplasia and restenosis. Animals were euthanized to isolate arteries for histomorphometric and immunohistochemical studies. Animals had graded levels of serum 25(OH)D; vitamin D-deficient (15.33 ± 1.45 ng/ml), vitamin D-sufficient + 1,000 IU oral vitamin D post-intervention (32.27 ± 1.20 ng/ml), and vitamin D-sufficient + 3,000 IU oral vitamin D post-intervention (51.00 ± 3.47 ng/ml). Findings from the OCT and histomorphometric studies showed a decrease in intimal hyperplasia and restenosis in vitamin D-supplemented compared to vitamin D-deficient swine. Vitamin D supplementation significantly decreased serum levels of TNF-α and IFN-γ, upregulated serum levels of IL-10, and had no effect on serum IL-6 levels. These findings suggest that vitamin D supplementation limits neointimal formation following coronary intervention in atherosclerotic swine and provide the support for vitamin D supplementation to protect against the development of coronary restenosis.
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Doença da Artéria Coronariana/cirurgia , Reestenose Coronária/prevenção & controle , Intervenção Coronária Percutânea , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/patologia , Deficiência de Vitamina D/tratamento farmacológico , Vitamina D/uso terapêutico , Animais , Doença da Artéria Coronariana/patologia , Reestenose Coronária/etiologia , Suplementos Nutricionais , Modelos Animais de Doenças , Hiperplasia/prevenção & controle , Intervenção Coronária Percutânea/efeitos adversos , Suínos , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/patologiaRESUMO
Vitamin D influences allergen-induced pathways in the innate and adaptive immune system, and its potential immunomodulatory role in allergic skin disorders has been explored. This comprehensive review article provides an overview of the role of vitamin D in three common dermatologic conditions: atopic dermatitis (AD), chronic urticaria, and allergic contact dermatitis (ACD). Whereas the literature regarding vitamin D and AD has resulted in mixed findings, several studies have described an inverse relationship between vitamin D levels and AD severity, and improvement in AD with vitamin D supplementation. Similarly, several studies report an inverse relationship between vitamin D levels and severity of chronic urticaria. Although current research in humans remains limited, an increased likelihood of ACD has been demonstrated in vitamin D-deficient mice. Additional well-designed clinical trials will be necessary to determine whether vitamin D supplementation should be recommended for prevention or adjuvant treatment of these common dermatologic conditions.
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Dermatite Alérgica de Contato/imunologia , Dermatite Atópica/imunologia , Urticária/imunologia , Deficiência de Vitamina D/imunologia , Vitamina D/metabolismo , Animais , Doença Crônica , Ensaios Clínicos como Assunto , Dermatite Atópica/dietoterapia , Suplementos Nutricionais , Progressão da Doença , Humanos , Camundongos , Vitamina D/uso terapêuticoRESUMO
Asthma is a chronic disease of the lung associated with airway hyperresponsiveness (AHR), airway obstruction and airway remodeling. Airway remodeling involves differentiation of airway epithelial cells into myofibroblasts via epithelial-mesenchymal transition (EMT) to intensify the degree of subepithelial fibrosis. EMT involves loss in E-cadherin with an increase in mesenchymal markers, including vimentin and N-cadherin. There is growing evidence that vitamin D has immunomodulatory and anti-inflammatory properties. However, the underlying molecular mechanisms of these effects are still unclear. In this study, we examined the contribution of vitamin D on the AHR, airway inflammation and expression of EMT markers in the airways of mice sensitized and challenged with a combination of clinically relevant allergens, house dust mite, ragweed, and Alternaria (HRA). Female Balb/c mice were fed with vitamin D-sufficient (2000 IU/kg) or vitamin D-supplemented (10,000 IU/kg) diet followed by sensitization with HRA. The density of inflammatory cells in the bronchoalveolar lavage fluid (BALF), lung histology, and expression of EMT markers by immunofluorescence were examined. Vitamin D-supplementation decreased AHR, airway inflammation in the BALF and the features of airway remodeling compared to vitamin D-sufficiency in HRA-sensitized and -challenged mice. This was accompanied with increased expression of E-cadherin and decreased vimentin and N-cadherin expression in the airways. These results indicate that vitamin D may be a beneficial adjunct in the treatment regime in allergic asthma.
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Alérgenos/imunologia , Suplementos Nutricionais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Vitamina D/farmacologia , Remodelação das Vias Aéreas/efeitos dos fármacos , Animais , Líquido da Lavagem Broncoalveolar , Caderinas/metabolismo , Citocinas/metabolismo , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Epitélio/patologia , Feminino , Imunoglobulina E/metabolismo , Inflamação/complicações , Inflamação/patologia , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Camundongos Endogâmicos BALB C , Hipersensibilidade Respiratória/complicações , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/patologia , Hipersensibilidade Respiratória/fisiopatologia , Vimentina/metabolismoRESUMO
Growing evidence suggests a pivotal role for vitamin D in cancers, particularly melanoma. The broad immunologic effects of vitamin D and its signaling axis make for a complex interplay between tumor cells and the immune system. Preclinical evidence suggests vitamin D to have protective effects in melanoma oncogenesis and progression, creating a potential role for vitamin D supplementation in cancer prevention and/or adjuvant therapy. In this commentary, the authors highlight studies of vitamin D in melanoma with clinical implications and call for large clinical trials to definitively determine the role of supplementation in patients to prevent and help treat melanoma.
RESUMO
Prospective epidemiological studies have consistently shown a relationship between vitamin D deficiency, insulin resistance, and type 2 diabetes mellitus (DM2). This is supported by recent trials showing that vitamin D supplementation in prediabetic or insulin-resistant patients with inadequate vitamin D levels improves insulin sensitivity. However, the molecular mechanisms underlying vitamin D deficiency-induced insulin resistance and DM2 remain unknown. Skeletal muscle insulin resistance is a primary defect in the majority of patients with DM2. Although sustained activation of forkhead box O1 (FOXO1) in skeletal muscle causes insulin resistance, a relationship between vitamin D deficiency and FOXO1 activation in muscle is unknown. We generated skeletal muscle-specific vitamin D receptor (VDR)-null mice and discovered that these mice developed insulin resistance and glucose intolerance accompanied by increased expression and activity of FOXO1. We also found sustained FOXO1 activation in the skeletal muscle of global VDR-null mice. Treatment of C2C12 muscle cells with 1,25-dihydroxyvitamin D (VD3) reduced FOXO1 expression, nuclear translocation, and activity. The VD3-dependent suppression of FOXO1 activation disappeared by knockdown of VDR, indicating that it is VDR-dependent. Taken together, these results suggest that FOXO1 is a critical target mediating VDR-null signaling in skeletal muscle. The novel findings provide the conceptual support that persistent FOXO1 activation may be responsible for insulin resistance and impaired glucose metabolism in vitamin D signaling-deficient mice, as well as evidence for the utility of vitamin D supplementation for intervention in DM2.
Assuntos
Proteína Forkhead Box O1/metabolismo , Resistência à Insulina , Músculo Esquelético/metabolismo , Deficiência de Vitamina D/metabolismo , Animais , Linhagem Celular , Núcleo Celular/metabolismo , Colecalciferol/metabolismo , Feminino , Deleção de Genes , Regulação da Expressão Gênica , Glucose/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/patologia , Especificidade de Órgãos , Transporte Proteico , Receptores de Calcitriol/deficiência , Receptores de Calcitriol/metabolismo , Deficiência de Vitamina D/patologiaRESUMO
Asthma is a chronic heterogeneous disorder, which involves airway inflammation, airway hyperresponsiveness (AHR) and airway remodeling. The airway smooth muscle (ASM) bundle regulates the broncho-motor tone and plays a critical role in AHR as well as orchestrating inflammation. Vitamin D deficiency has been linked to increased severity and exacerbations of symptoms in asthmatic patients. It has been shown to modulate both immune and structural cells, including ASM cells, in inflammatory diseases. Given that current asthma therapies have not been successful in reversing airway remodeling, vitamin D supplementation as a potential therapeutic option has gained a great deal of attention. Here, we highlight the potential immunomodulatory properties of vitamin D in regulating ASM function and airway inflammation in bronchial asthma.