Vitamin D Suppression of Endoplasmic Reticulum Stress Promotes an Antiatherogenic Monocyte/Macrophage Phenotype in Type 2 Diabetic Patients

Riek, Amy E.; Oh, Junseo; Sprague, Jennifer; Timpson, A.; Fuentes, Lisa de las; Bernal‐Mizrachi, Leon; Schechtman, Kenneth B.; Bernal‐Mizrachi, Carlos

doi:10.1074/jbc.m112.386912

Cited by 108 publications

(94 citation statements)

References 60 publications

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“…This resulted from downregulation of JNK activity, improved insulin signaling, reduced oxidized LDL-derived cholesterol uptake, as well as suppression of macrophage endoplasmic reticulum (ER) stress and promotion of an antiatherogenic monocyte/macrophage phenotype (51,59). More recently, Szeto et al (66) showed that VDR deficiency (i.e., VDR Ϫ/Ϫ genetic background) accelerated the atherosclerotic process in the low-density lipoprotein receptor-deficient (LDLR Ϫ/Ϫ ) mouse.…”

Section: Expression Of Vdr and 1␣-hydroxylase Genes In Heartmentioning

confidence: 95%

Vitamin D and the heart

Gardner

Chen

Glenn

2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Vitamin D receptors (VDR) are found in cells throughout the cardiovascular system. A variety of experimental studies indicate that the liganded VDR may play an important role in controlling cardiac hypertrophy and fibrosis, regulating blood pressure, and suppressing the development of atherosclerosis. Some, but not all, observational studies in humans provide support for these experimental findings, raising the possibility that vitamin D or its analogs might prove useful therapeutically in the prevention or treatment of cardiovascular disease.

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Section: Expression Of Vdr and 1␣-hydroxylase Genes In Heartmentioning

confidence: 95%

Vitamin D and the heart

Gardner

Chen

Glenn

2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…90 Moreover, 1a,25(OH) 2 D 3 acting as a natural endoplasmic reticulum stress reliever was found to induce an M1 antiatherogenic macrophage/monocyte phenotype over M2 (with increased cholesterol uptake and deposition) and to decrease mRNA expression of the monocyte adhesion molecules PSGL-1, β(1)-integrin, and β(2)-integrin, resulting in an increase of monocyte adhesion to activated endothelium. 91 Moreover, 1a,25(OH) 2 D 3 dose-dependently inhibited the production of IL-6 and TNF-α by monocytes, an effect exerted at a posttranscriptional level, and possibly contributed to the aforementioned suppression of Th1 proatherogenic immune response. 92 In addition to their immunoregulatory effects, monocytes are implicated in the development of atherothrombotic lesions by regulating coagulant and anticoagulant factors.…”

Section: Effects Of Vitamin D On Immune Cellsmentioning

confidence: 99%

Role of Vitamin D in Atherosclerosis

et al. 2013

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A therosclerosis, the principal cause of cardiovascular diseases (CVDs), is a process that involves a complex interplay among different factors and cell types, including cells of the immune system (T cells, B cells, natural killer cells, monocytes/macrophages, dendritic cells) and cells of the vessel wall (endothelial cells [ECs], vascular smooth muscle cells [VSMCs]). The atherogenic process evolves in different stages, starting from inflammatory endothelial activation/ dysfunction and resulting in plaque vulnerability and rupture. Vitamin D deficiency affects almost 50% of the population worldwide. It has been suggested that this pandemic might contribute to the worldwide increased prevalence of CVD. 9-11Several mechanisms have been proposed to account for this inverse relationship. In addition to its effects exerted on numerous tissues and organs that indirectly participate in the atherosclerosis, vitamin D is directly involved in this systemic inflammatory process.12,13 Vitamin D receptors (VDRs) are present in all cells implicated in atherosclerosis, including ECs, VSMCs, and immune cells. Vitamin D appears to regulate a wide range of physiological and pathological processes like vascular cell growth, migration, and differentiation; immune response modulation; cytokine expression; and inflammatory and fibrotic pathways, all of which play a crucial role, starting from the early stage of endothelial activation/dysfunction to the later stages of the plaque vulnerability and rupture.In this review, we provide current data on the effects of vitamin D on cells directly implicated in atherosclerosis such as ECs, VSMCs, and immune cells (lymphocytes, monocytes, macrophages, etc) with a focus on the underlying molecular mechanisms, which are still largely unknown. We also summarize reports related to the favorable (antiatherogenic) actions of vitamin D in tissues and organs that indirectly participate in the atherogenic process. Finally, we critically discuss clinical studies to assess the protective role of vitamin D and the efficacy of vitamin D and VDR agonists in CVD. Because a comprehensive background is a prerequisite for further discussions of vitamin D-induced effects, we provide a brief description of vitamin D metabolism and mechanism of action. Vitamin D Metabolism and Mechanism of ActionVitamin D is a steroid hormone that comes in 2 forms that differ chemically in their side chain, D 2 and D 3 (Figure 1). Either produced in the skin (D 3 ) from 7-dehydrocholesterol by exposure to ultraviolet-B light or ingested with foods of plant or animal origin (D 2 and D 3 , respectively), vitamin D is biologically inert and requires 2 hydroxylations to form its active metabolite. 10 The first hydroxylation is constitutive and takes place in the liver by vitamin D-25-hydroxylase to form 25(OH)D. The second hydroxylation is catalyzed by 25(OH) D-1aOHase (CYP27B1) to form the biologically active form of vitamin D, 1,25(OH) 2 D (calcitriol; see Figure 1). This latter 1a-hydroxylation of 25(OH)D takes place in most tiss...

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“…Stimulation of ER stress induces responses to improve protein folding, but persistent stress triggers further inflammation through NF-kB and c-Jun N-terminal kinase activation (JNK) activation, increasing foam cell formation and inducing plaque necrosis in advanced atherosclerotic lesions (Hotamisligil, 2006; Ozcan and Tabas, 2010). Vitamin D is a natural macrophage ER stress reliever (Riek et al, 2012). Vitamin D receptor (VDR) is present in almost all cells of the immune system, and vitamin D deficiency is widely prevalent and has emerged as a potential contributor to the pathophysiology of T2DM and CVD (Holick, 2007; Norman and Powell, 2014; Veldman et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Deletion of Macrophage Vitamin D Receptor Promotes Insulin Resistance and Monocyte Cholesterol Transport to Accelerate Atherosclerosis in Mice

et al. 2015

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Summary Intense effort has been devoted to understanding predisposition to chronic systemic inflammation as this contributes to cardiometabolic disease. We demonstrate that deletion of the macrophage vitamin D receptor (VDR) in mice (KODMAC) is sufficient to induce insulin resistance by promoting M2 macrophage accumulation in the liver, as well as increase cytokine secretion and hepatic glucose production. Moreover, VDR deletion increases atherosclerosis by enabling lipid-laden M2 monocytes to adhere, migrate, and carry cholesterol into the atherosclerotic plaque, and by increasing macrophage cholesterol uptake and esterification. Increased foam cell formation results from lack of VDR-SERCA2b interaction, causing SERCA dysfunction, activation of ER stress-CaMKII-JNKp-PPARγ signaling, and induction of the scavenger receptors CD36 and SR-A1. BM transplant of VDR-expressing cells into KODMAC mice improved insulin sensitivity, suppressed atherosclerosis, and decreased foam cell formation. The immunomodulatory effects of vitamin D in macrophages are thus critical in diet-induced insulin resistance and atherosclerosis in mice. Graphical Abstract

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Vitamin D Suppression of Endoplasmic Reticulum Stress Promotes an Antiatherogenic Monocyte/Macrophage Phenotype in Type 2 Diabetic Patients

Cited by 108 publications

References 60 publications

Vitamin D and the heart

Vitamin D and the heart

Role of Vitamin D in Atherosclerosis

Deletion of Macrophage Vitamin D Receptor Promotes Insulin Resistance and Monocyte Cholesterol Transport to Accelerate Atherosclerosis in Mice

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