The vitamin D receptor activator paricalcitol prevents fibrosis and diastolic dysfunction in a murine model of pressure overload

Meems, Laura M.G.; Cannon, Megan V.; Mahmud, Hasan; Voors, Adriaan A.; Gilst, Wiek H. van; Silljé, Herman H W; Ruifrok, W. P.; Boer, Rudolf A. de

doi:10.1016/j.jsbmb.2012.06.004

Cited by 75 publications

(65 citation statements)

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“…Secondly, these indices may have been increased in association with deterioration of left ventricular intrinsic diastolic properties. Experimental studies have shown that vitamin D exerts a protective effect against left ventricular diastolic dysfunction by inhibiting myocardial fibrosis and promoting cardiac relaxation through modulation of myocardial calcium handling 2, 19. Previous studies have shown the presence of myocardial fibrosis and altered myocardial calcium handling in dogs with CVHD,20, 21 and the contribution of vitamin D to such myocardial changes still needs to be clarified.…”

Section: Discussionmentioning

confidence: 99%

“…Previous experimental studies have shown that cardiac contractility is enhanced by vitamin D through modulation of intracellular calcium metabolism 2, 19. Furthermore, clinical trials in humans have demonstrated that the left ventricular systolic function of heart failure patients with vitamin D deficiency improves with supplementation of vitamin D 8, 9.…”

Section: Discussionmentioning

confidence: 99%

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Vitamin D Status in Different Stages of Disease Severity in Dogs with Chronic Valvular Heart Disease

Osuga

Nakamura

Morita

et al. 2015

Veterinary Internal Medicne

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BackgroundIn humans with heart disease, vitamin D deficiency is associated with disease progression and a poor prognosis. A recent study showed that serum 25‐hydroxyvitamin D [25(OH)D] concentration, the hallmark of vitamin D status, was lower in dogs with heart failure than in normal dogs, and a low concentration was associated with poor outcome in dogs with heart failure.ObjectivesTo elucidate the vitamin D status of dogs with chronic valvular heart disease (CVHD) at different stages of disease severity.AnimalsForty‐three client‐owned dogs with CVHD.MethodsIn this cross‐sectional study, dogs were divided into 3 groups (14 dogs in Stage B1, 17 dogs in Stage B2, and 12 dogs in Stage C/D) according to ACVIM guidelines. Dogs underwent clinical examination including echocardiography. Serum 25(OH)D concentrations were measured in each dog.ResultsSerum 25(OH)D concentration was significantly lower in Stage B2 (median, 33.2 nmol/L; range, 4.9–171.7 nmol/L) and C/D (13.1 nmol/L; 4.9–58.1 nmol/L) than in Stage B1 (52.5 nmol/L; 33.5–178.0 nmol/L) and was not significantly different between Stage B2 and Stage C/D. Among clinical variables, there were significant negative correlations between 25(OH)D concentration and both left atrial‐to‐aortic root ratio and left ventricular end‐diastolic diameter normalized for body weight.Conclusions and Clinical ImportanceThese results indicate that vitamin D status is associated with the degree of cardiac remodeling, and the serum 25(OH)D concentration begins to decrease before the onset of heart failure in dogs with CVHD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Vitamin D Status in Different Stages of Disease Severity in Dogs with Chronic Valvular Heart Disease

Osuga

Nakamura

Morita

et al. 2015

Veterinary Internal Medicne

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“…Clinical treatment with active VitD is typically accompanied by hypercalcemic side effects (17), therefore, VitD analogs with fewer side effects may provide therapeutic benefits. A previous clinical study demonstrated that treatment with paricalcitol, which is a VitD analog, was able to safely reduce residual albuminuria in patients with DN (18).…”

Section: Introductionmentioning

confidence: 99%

“…Treatment with 1,25-(OH) 2 D 3 (also known as calcitriol) or its analogs is able to repress the expression of α-SMA and collagen I in a unilateral ureteral occlusion model and cultured HK-2 cells (19,20). The renoprotective role of 1,25-(OH) 2 D 3 and its analogs have been demonstrated to be associated with anti-inflammation, renin-angiotensin system (RAS) inhibition and prevention of EMT (17,(20)(21)(22). By binding to the VDR, 1,25-(OH) 2 D 3 recruits cofactors to form a transcriptional complex which subsequently binds to VitD response elements in the promoter region of target genes, altering transcriptional events within target cells (17,20,23).…”

Section: Introductionmentioning

confidence: 99%

1,25-(OH)2D3 and its analogue BXL-628 inhibit high glucose-induced activation of RhoA/ROCK pathway in HK-2 cells

Zhang

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. It has previously been reported that 1,25-(OH) 2 D 3 inhibits high glucose-induced epithelial-to-mesenchymal transition (EMT) in HK-2 cells. However, the mechanism of this renoprotective action remains unclear. Elocalcitol (BXL-628), a vitamin D analog, has been suggested to be effective on the RhoA/Rho associated protein kinase (ROCK) pathway, which serves a crucial role in high glucose-induced EMT. The aim of the present study was to investigate the effect of 1,25-(OH) 2 D 3 and its analogue BXL-628 on high glucose-induced activation of the RhoA/ROCK pathway in human renal proximal tubular cells. HK-2 cells were co-treated with high glucose and either 1,25-(OH)2D3 or BXL-628. The RhoA expression levels and ROCK activity of the membrane were assessed via western blot analysis or immunofluorescence. α-smooth muscle actin (α-SMA) and epithelial (E)-cadherin were detected using western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), whereas collagen I and fibronectin levels were measured by ELISA and RT-qPCR. The results demonstrated that 1,25-(OH) 2 D 3 and BXL-628 both significantly downregulated the expression of active RhoA and ROCK activity induced by high glucose (P<0.05). Furthermore, the expressions of α-SMA, collagen I, and fibronectin were significantly downregulated at both protein and mRNA (P<0.05) levels, whereas the expression of E-cadherin was significantly increased (P<0.05) by 1,25-(OH) 2 D 3 or BXL-628 treatment. In conclusion, the vitamin D receptor agonist 1,25-(OH) 2 D 3 and its analogue BXL-628 were both able to attenuate high glucose-induced EMT and extracellular matrix accumulation of HK-2 cells by suppressing the RhoA/ROCK signaling pathway in vitro.

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“…The inhibition of the canonical Wnt signaling pathway promoted by 1,25-D 3 could ameliorate the fibrotic process. Moreover, our group shown previously that 1,25-D 3 is a potent anti-fibrotic factor promoting the decrease expression of TGF-β, PAI-1 and several collagen isoforms in mesenchymal multipotent cells There is an in vivo study showing that vitamin D deficiency results in maladaptive cardiac remodeling attributable to progressive myocyte hypertrophy and interstitial fibrosis (Meems et al, 2012). A recent study by our group did show repletion of hypovitaminosis D in humans led to down-regulation of protein expression in abdomen fat biopsies for tumor necrosis factor alpha, IFN gamma, interleukin 6 and soluble intercellular adhesion molecule-1 (sICAM-1), a biomarker of inflammatory process associated with endothelial damage and platelet activation, supporting an in vivo role for vitamin D in related signaling pathways (Martins et al 2014).…”

Section: Discussionmentioning

confidence: 98%

1,25-vitamin D3 promotes cardiac differentiation through modulation of the WNT signaling pathway

Hlaing

Garcia

Contreras

et al. 2015

EJEA

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Cardiovascular disease (CV) remains the leading cause of death worldwide. Low levels of vitamin D are associated with high risk of myocardial infarction, even after controlling for factors associated with coronary artery disease. A growing body of evidence suggests that vitamin D plays an important role in CV related signaling pathways. However, little is known about the molecular mechanism by which vitamin D modulates cardiac development. The Wnt signaling pathway plays a pivotal role in tissue development by controlling stem cell renewal, lineage selection and even more importantly heart development. In this study, we examined the role of 1,25-D 3 (active form of vitamin D) on cardiomyocyte proliferation, apoptosis, cell phenotype, cell cycle progression and differentiation into cardiomyotubes. We determined that the addition of 1,25-D 3 to cardiomyocytes cells: 1) Inhibits cell proliferation without promoting apoptosis; 2) Decreases expression of genes related to the regulation of the cell cycle; 3) Promotes cardiomyotubes formation; 4) Induces the expression of Casein kinase-1-α1, a negative regulator of the canonical Wnt signaling pathway; and 5) Increases the expression of the noncanonical Wnt11, which it has been demonstrated to induce cardiac differentiation during embryonic development in adult cells. In conclusion, we postulate that vitamin D promotes cardiac differentiation through a negative modulation of the canonical Wnt signaling pathway and by upregulating the expression of Wnt11. These results suggest that vitamin D repletion to prevent and/or improve cardiovascular disorders that are linked to abnormal cardiac differentiation, such as post infarction cardiac remodeling, deserve further study.

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The vitamin D receptor activator paricalcitol prevents fibrosis and diastolic dysfunction in a murine model of pressure overload

Cited by 75 publications

References 50 publications

Vitamin D Status in Different Stages of Disease Severity in Dogs with Chronic Valvular Heart Disease

Vitamin D Status in Different Stages of Disease Severity in Dogs with Chronic Valvular Heart Disease

1,25-(OH)2D3 and its analogue BXL-628 inhibit high glucose-induced activation of RhoA/ROCK pathway in HK-2 cells

1,25-vitamin D3 promotes cardiac differentiation through modulation of the WNT signaling pathway

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