In vivo endothelial gene regulation in diabetes

Maresh, J. Gregory; Shohet, Ralph V.

doi:10.1186/1475-2840-7-8

Cited by 15 publications

(17 citation statements)

References 25 publications

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“…While most studies of the cardioprotective effects of adiponectin in both humans and mouse models have largely correlated these effects with circulating concentrations [48], several studies suggest that locally produced adiponectin also contributes to the cardioprotective effect of this hormone. Although adiponectin was originally thought to be exclusively secreted by adipose tissue, our study, in addition to a growing body of evidence, reveals that other cells types can express and secrete adiponectin and that this local signaling has functional significance [36-42, 49]. …”

Section: Discussionmentioning

confidence: 99%

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Vascular smooth muscle cell-derived adiponectin: A paracrine regulator of contractile phenotype

Ding

Carrao

Wagner

et al. 2012

Journal of Molecular and Cellular Cardiology

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Adiponectin is a cardioprotective adipokine derived predominantly from visceral fat. We recently demonstrated that exogenous adiponectin induces vascular smooth muscle cell (VSMC) differentiation via repression of mTORC1 and FoxO4. Here we report for the first time that VSMC express and secrete adiponectin, which acts in an autocrine and paracrine manner to regulate VSMC contractile phenotype. Adiponectin was found to be expressed in human coronary artery and mouse aortic VSMC. Importantly, siRNA knock-down of endogenous adiponectin in VSMC significantly reduced the expression of VSMC contractile proteins. Contractile protein deficiency was also observed in primary VSMC isolated from Adiponectin-/- mice. This deficiency could be rescued by culturing Adiponectin-/- VSMC in conditioned media from wild type (WT) VSMC. Moreover, the paracrine effect of VSMC-derived adiponectin was confirmed as adiponectin neutralizing antibody blocked the rescue. Overexpressed adiponectin also exerted paracrine effects on neighboring untransfected VSMC, which was also blocked by adiponectin neutralizing antibody. Interestingly, adiponectin expression was inducible by the PPARγ agonist rosiglitazone. Our data support an important role for VSMC-derived adiponectin in maintaining VSMC contractile phenotype, contributing to critical cardioprotective functions in the vascular wall.

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Section: Discussionmentioning

confidence: 99%

“…However, several recent publications suggested that adiponectin is also expressed in cardiomyocytes, skeletal muscle, bone-forming cells, placenta, liver, and pituitary cells [36-42]. Whether vascular smooth muscle expresses and secretes functional adiponectin is not known.…”

Section: Introductionmentioning

confidence: 99%

Vascular smooth muscle cell-derived adiponectin: A paracrine regulator of contractile phenotype

Ding

Carrao

Wagner

et al. 2012

Journal of Molecular and Cellular Cardiology

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“…Tissues were placed into ice-cold PBS and freed of adherent fat. The aortic and skeletal muscle tissues from three animals were each pooled, minced into 1 mm fragments, and dispersed as previously described (24,25). Suspensions of collagenolytically separated cells were incubated with anti-mouse CD16/32 (1:500) for 5 min and then with phycoerythrin-conjugated anti-mouse CD31 (1:200) for 25 min on ice (eBiosciences cat.…”

Section: Animals and Dietmentioning

confidence: 99%

“…However, an in vitro analysis may only partially reflect the complex in vivo state, where numerous hormonal, metabolic, and cellular perturbations combine to influence the endothelial cell. In vivo analysis of aortic endothelium from mice exposed to a Type I, insulin-deficient, model of diabetes revealed dysregulation of transcripts involved in inflammation and insulin sensitivity (24). Here, we study mice rendered diabetic by a high-fat diet (HFD) and comprehensively evaluate arterial as well as capillary endothelial transcriptional responses in a model of Type II, insulin resistant, diabetes.…”

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confidence: 99%

Transcriptional analysis of the endothelial response to diabetes reveals a role for galectin-3

Darrow

Shohet

Maresh

2011

Physiological Genomics

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Darrow AL, Shohet RV, Maresh JG. Transcriptional analysis of the endothelial response to diabetes reveals a role for galectin-3. Physiol Genomics 43: 1144 -1152, 2011. First published July 26, 2011 doi:10.1152/physiolgenomics.00035.2011.-To characterize the endothelial dysfunction associated with Type II diabetes, we surveyed transcriptional responses in the vascular endothelia of mice receiving a diabetogenic, high-fat diet. Tie2-GFP mice were fed a diet containing 60% fat calories (HFD); controls were littermates fed normal chow. Following 4, 6, and 8 wk, aortic and leg muscle tissues were enzymatically dispersed, and endothelial cells were obtained by fluorescence-activated cell sorting. Relative mRNA abundance in HFD vs. control endothelia was measured with long-oligo microarrays; highly dysregulated genes were confirmed by real-time PCR and protein quantification. HFD mice were hyperglycemic by 2 wk and displayed vascular insulin resistance and decreased glucose tolerance by 5 and 6 wk, respectively. Endothelial transcripts upregulated by HFD included galectin-3 (Lgals3), 5-lipoxygenase-activating protein, and chemokine ligands 8 and 9. Increased LGALS3 protein was detected in muscle endothelium by immunohistology accompanied by elevated LGALS3 in the serum of HFD mice. Our comprehensive analysis of the endothelial transcriptional response in a model of Type II diabetes reveals novel regulation of transcripts with roles in inflammation, insulin sensitivity, oxidative stress, and atherosclerosis. Increased endothelial expression and elevated humoral levels of LGALS3 supports a role for this molecule in the vascular response to diabetes, and its potential as a direct biomarker for the inflammatory state in diabetes. gene expression; microarray; vascular biology; endothelial dysfunction; metabolic syndrome TYPE II DIABETES IS ASSOCIATED with increased atherosclerosis, retinopathy, skin ulceration, and other vascular-related diseases, all of which may involve damaged or dysfunctional endothelium. A major consequence of diabetes is endothelial exposure to elevated glucose and fatty acids, leading to endothelial nitric oxide synthase uncoupling and subsequent generation of reactive oxygen and nitrogen species (46) as well as the formation of advanced glycation end-products (AGEs) (45). Furthermore, hyperinsulinemia and other hormonal changes can alter endothelial signaling pathways (34). These changes may promote inflammation, impair vasoregulation, disrupt hemostasis, and inhibit reverse cholesterol transport (2, 32). By examining the transcriptional changes that occur in both the micro-and macrovascular endothelium of mice exposed to a dietary model of Type II diabetes, we expect to gain further insight into the underlying mechanisms of the endothelial dysfunction characteristic of diabetes and the metabolic syndrome.Transcriptional analysis has been used to examine the responses of cultured endothelium exposed to high glucose and insulin (9, 44). However, an in vitro analysis may only partially reflect the co...

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“…Up-regulation of Slc36a2 was also reported in the endothelium of diabetic mice [47], suggesting utilization of amino acids as alternative energy substrates. In addition, BBdp rats fed the control diet had lower mRNA levels of Kcnj13 (0.64-fold), a potassium transporter [48], than BBc rats fed the control diet, and the high-iodine diet down-regulated Kcnj13 mRNA expression in both BBc and BBdp rats.…”

Section: Discussionmentioning

confidence: 89%

Excess dietary iodine differentially affects thyroid gene expression in diabetes, thyroiditis‐prone versus ‐resistant BioBreeding (BB) rats

Swist

Chen

Qiao

et al. 2011

Molecular Nutrition Food Res

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In vivo endothelial gene regulation in diabetes

Cited by 15 publications

References 25 publications

Vascular smooth muscle cell-derived adiponectin: A paracrine regulator of contractile phenotype

Vascular smooth muscle cell-derived adiponectin: A paracrine regulator of contractile phenotype

Transcriptional analysis of the endothelial response to diabetes reveals a role for galectin-3

Excess dietary iodine differentially affects thyroid gene expression in diabetes, thyroiditis‐prone versus ‐resistant BioBreeding (BB) rats

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