Calcitriol restores renovascular function in estrogen-deficient rats through downregulation of cyclooxygenase-2 and the thromboxane-prostanoid receptor

Dong, Jiajia; Wong, Siu Ling; Lau, Chi Wai; Liu, Jian; Wang, Yixiang; He, Zhen Dan; Ng, Chi Fai; Chen, Zhen Yu; Yao, Xiaoqiang; Xu, Aimin; Ni, Xiaochen; Wang, Hongyan; Huang, Yü

doi:10.1038/ki.2013.12

Cited by 31 publications

(26 citation statements)

References 47 publications

(52 reference statements)

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“…Therefore, it is suggested that ELD may prevent endothelial dysfunction through the reduction of oxidative stress via normalization of vascular PPARg/NFkB pathway in OVX rats. These beneficial effects of ELD correspond to previous report that calcitriol restored renovascular function in OVX rats (Dong et al 2013). In addition, this is the first report indicated that in vivo endothelial function was evaluated by measurement of FMD under the study design, in which ELD could prevent bone loss in OVX rats.…”

Section: Discussionsupporting

confidence: 64%

Eldecalcitol prevents endothelial dysfunction in postmenopausal osteoporosis model rats

Serizawa¹,

Tashiro²,

Takeda

et al. 2015

Journal of Endocrinology

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Postmenopausal women have high incidence of cardiovascular events as estrogen deficiency can cause endothelial dysfunction. Vitamin D is reported to be beneficial on endothelial function, but it remains controversial whether vitamin D is effective for endothelial dysfunction under the treatment for osteoporosis in postmenopausal women. The aim of this study was to evaluate the endothelial protective effect of eldecalcitol (ELD) in ovariectomized (OVX) rats. ELD (20 ng/kg) was orally administrated five times a week for 4 weeks from 1 day after surgery. After that, flow-mediated dilation (FMD) as an indicator of endothelial function was measured by high-resolution ultrasound in the femoral artery of living rats. ELD ameliorated the reduction of FMD in OVX rats. ELD inhibited the increase in NOX4, nitrotyrosine, and p65 and the decrease in dimer/monomer ratio of nitric oxide synthase in OVX rat femoral arteries. ELD also prevented the decrease in peroxisome proliferator-activated receptor gamma (PPARg) in femoral arteries and cultured endothelial cells. Although PPARg is known to inhibit osteoblastogenesis, ELD understandably increased bone mineral density of OVX rats without increase in PPARg in bone marrow. These results suggest that ELD prevented the deterioration of endothelial function under condition of preventing bone loss in OVX rats. This endothelial protective effect of ELD might be exerted through improvement of endothelial nitric oxide synthase uncoupling, which is mediated by an antioxidative effect through normalization of vascular PPARg/NF-kB signaling.

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Section: Discussionsupporting

confidence: 64%

Eldecalcitol prevents endothelial dysfunction in postmenopausal osteoporosis model rats

Serizawa¹,

Tashiro²,

Takeda

et al. 2015

Journal of Endocrinology

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“…Primary rat aortic endothelial cells were cultured as previously described [25]. Briefly, aortas were isolated, cut open longitudinally, and digested with 0.2% collagenase directed against type 1A collagen (Sigma-Aldrich) for 15 min in a 37°C shaking water bath.…”

Section: Methodsmentioning

confidence: 99%

Tetramethylpyrazine Protects against Hydrogen Peroxide‐Provoked Endothelial Dysfunction in Isolated Rat Aortic Rings: Implications for Antioxidant Therapy of Vascular Diseases

Wong

et al. 2014

Evidence-Based Complementary and Alternative Medicine

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Background and Objectives. Oxidative stress can initiate endothelial dysfunction and atherosclerosis. This study evaluated whether tetramethylpyrazine (TMP), the predominant active ingredient in Rhizoma Ligustici Wallichii (chuanxiong), prevents endothelial dysfunction in a rat model of oxidative stress. Methods. Isolated rat aortic rings were pretreated with various drugs before the induction of endothelial dysfunction by hydrogen peroxide (H2O2). Changes in isometric tension were then measured in acetylcholine- (ACh-) relaxed rings. Endothelial nitric oxide synthase (eNOS) expression was evaluated in the rings by Western blotting, and superoxide anion (O2 ∙−) content was assessed in primary rat aortic endothelial cells by dihydroethidium- (DHE-) mediated fluorescence microscopy. Results. ACh-induced endothelium-dependent relaxation (EDR) was disrupted by H2O2 in endothelium-intact aortic rings. H2O2-impaired relaxation was ameliorated by acute pretreatment with low concentrations of TMP, as well as by pretreatment with catalase and the NADPH oxidase inhibitors, apocynin and diphenyleneiodonium (DPI). TMP, apocynin, and DPI also reduced O2 ∙− accumulation in endothelial cells,but TMP failed to alter eNOS expression in aortic rings incubated with H2O2. Conclusions. TMP safeguards against oxidative stress-induced endothelial dysfunction, suggesting that the agent might find therapeutic utility in the management of vascular diseases. However, TMP's role in inhibiting NADPH oxidase and its vascular-protective mechanism of action requires further investigation.

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“…Similar results were observed in ex-vivo rat renal arteries treated with U46619, a thromboxane A2 agonist. Here, TEI9647 reduced the phosphorylation of endothelial nitric oxide synthase and levels of NO that were elevated in the presence of 1,25-(OH) 2 D 3 (89). In respect to cancer, TEI9647 reversed the down-regulation of CYP21A2 in the presence of 1,25-(OH) 2 D 3 in a reporter assay using mouse and human adrenocortical carcinoma cells (90).…”

Section: Vdr Antagonists or Allosteric Inhibition Of The Vdr–coregmentioning

confidence: 91%

Inhibitors for the Vitamin D Receptor–Coregulator Interaction

Teske

2016

Vitamin D Hormone

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The vitamin D receptor (VDR) belongs to the superfamily of nuclear receptors and is activated by the endogenous ligand 1,25-dihydroxyvitamin D3. The genomic effects mediated by VDR consist of the activation and repression of gene transcription, which includes the formation of multi-protein complexes with coregulator proteins. Coregulators bind many nuclear receptors and can be categorized according their role as coactivators (gene activation) or corepressors (gene repression). Herein, different approaches to develop compounds that modulate the interaction between VDR and coregulators are summarized. This include coregulator peptides that were identified by creating phage display libraries. Subsequent modification of these peptides including the introduction of a tether or non-hydrolysable bonds resulted in the first direct VDR–coregulator inhibitors. Later, small molecules that inhibit VDR–coregulator inhibitors were identified using rational drug design and high throughput screening. Early on, allosteric inhibition of VDR–coregulator interactions was achieved with VDR antagonists that change the conformation of VDR and modulate the interactions with coregulators. A detailed discussion of their dual agonist/antagonist effects is given as well as a summary of their biological effects in cell-based assays and in vivo studies.

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Calcitriol restores renovascular function in estrogen-deficient rats through downregulation of cyclooxygenase-2 and the thromboxane-prostanoid receptor

Cited by 31 publications

References 47 publications

Eldecalcitol prevents endothelial dysfunction in postmenopausal osteoporosis model rats

Eldecalcitol prevents endothelial dysfunction in postmenopausal osteoporosis model rats

Tetramethylpyrazine Protects against Hydrogen Peroxide‐Provoked Endothelial Dysfunction in Isolated Rat Aortic Rings: Implications for Antioxidant Therapy of Vascular Diseases

Inhibitors for the Vitamin D Receptor–Coregulator Interaction

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