Altered paracrine effect of endothelin in blood vessels of the hyperinsulinemic, insulin resistant obese Zucker rat

Wu, Shengjun; Hopfner, Rob L; McNeill, J. Robert; Wilson, Thomas W.; Gopalakrishnan, Venkat

doi:10.1016/s0008-6363(99)00417-4

Cited by 52 publications

(39 citation statements)

References 26 publications

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“…In galactose-fed rats, augmented extracellular matrix production was partially prevented by endothelin receptor blockade (25). Finally, in mesenteric artery and thoracic aorta from spontaneously insulin-resistant obese Zucker rats, increased endothelin receptor mRNA expression and receptor levels were noted (13). These findings are consistent with the current results in that they suggest an association between insulin resistance/hyperinsulinemia and endothelin-mediated vascular dysfunction.…”

Section: Et-1 and Vascular Dysfunction In Insulin Resistancesupporting

confidence: 90%

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Endothelin Contributes to Basal Vascular Tone and Endothelial Dysfunction in Human Obesity and Type 2 Diabetes

et al. 2002

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Endothelium-dependent vasodilation is impaired in clinical states of insulin resistance such as obesity and type 2 diabetes. Individuals who have hyperinsulinemic insulin resistance have relatively elevated circulating levels of endothelin (ET)-1, suggesting that ET-1 may be important in the endothelial dysfunction and alterations of vascular tone in these conditions. In 8 lean subjects, 12 nondiabetic obese subjects, and 8 subjects with type 2 diabetes, we measured basal and methacholine-stimulated rates of leg blood flow (LBF) and total serum nitrates (NOx) before and after the intrafemoral arterial administration of BQ123, a specific blocker of ET A receptors. BQ123 produced significant vasodilation in the obese and type 2 diabetic subjects (leg vascular resistance ‫؍‬ mean arterial pressure/LBF fell by 34 and 36%; P < 0.005) but not in the lean subjects (13%; P ‫؍‬ NS, P ‫؍‬ 0.018 comparing all groups). ET A blockade did not change basal NOx flux (NOx*LBF). This suggests increased basal ET-1 constrictor tone among obese and type 2 diabetic subjects. BQ123 corrected the baseline defect in endothelium-dependent vasodilation seen in obese and type 2 diabetic subjects, suggesting an important contribution of ET-1 to endothelial dysfunction in these subjects. In contrast to basal conditions, stimulated NOx flux was augmented by BQ123 in obese and type 2 diabetic subjects but not in L subjects (P ‫؍‬ 0.04), suggesting a combined effect of ET A blockade to reduce constrictor tone and augment dilator tone. Endothelin seems to contribute to endothelial dysfunction and the regulation of vascular tone in human obesity and type 2 diabetes. Diabetes 51: [3517][3518][3519][3520][3521][3522][3523] 2002 T he endothelial dysfunction observed in the insulin-resistant states of obesity and type 2 diabetes has been attributed to decreased nitric oxide (NO) availability (1,2), likely related to both impaired production and increased consumption (3,4). However, paracrine control of vascular tone depends on the balance of both vasodilating and vasoconstricting factors (5). Endothelin (ET)-1, produced directly by vascular endothelial cells, is the most important locally produced vasoconstrictor, acting principally through type A (ET A ) receptors on vascular smooth muscle cells (6). ET-1 and NO function as mutual antagonists in the determination of vascular tone but also have important direct interactions at the level of transcription and expression (7) and signal transduction (8), with each acting to limit the net production of the other. This mutual antagonism can serve to amplify any imbalances resulting from other factors, for example insulin resistance/hyperinsulinemia. Furthermore, both ET-1 and NO have effects beyond their contributions to the regulation of vascular tone, which act in net as antiatherosclerotic (NO) or proatherosclerotic (ET-1) factors through modulation of platelet activity, lipid oxidation, leukocyte chemotaxis, and local production of thrombotic factors as well as the growth and proliferation of vascul...

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Section: Et-1 and Vascular Dysfunction In Insulin Resistancesupporting

confidence: 90%

“…Although data from animal models of insulin resistance and diabetes suggest an important role for ET-1 in the associated vascular dysfunction (11)(12)(13), little is known about the contributions of ET-1 to vascular dysfunction in human obesity and type 2 diabetes. Insulin engenders the production and release of ET-1 in vitro (14,15).…”

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confidence: 99%

Endothelin Contributes to Basal Vascular Tone and Endothelial Dysfunction in Human Obesity and Type 2 Diabetes

et al. 2002

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“…The subdivision in fasted and hyperglycemic rats stressed the higher levels of expression of the genes analyzed in the lung tissue of hyperglycemic rats compared to those in the fasting group, confirming that glucose can interfere with the production of ET-1, by stimulation, as previously reported (Wu et al, 2000). We also observed increased levels of DNA damage, in the form of DSB, in the lungs of obese rats.…”

Section: Discussionsupporting

confidence: 90%

Transcriptional Alterations of ET-1 Axis and DNA Damage in Lung Tissue of a Rat Obesity Model

Cabiati

Salvadori

et al. 2015

DNA and Cell Biology

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Obesity has been implicated in the development of many cancers. This can lead to genome damage, especially in the form of double-strand break, the presence of which is now easily detected through nuclear phosphorylation of histone H2AX (g-H2AX) focus assay. Recently, the endothelin (ET) axis has also been shown to have a role in the growth and progression of several tumors, including lung cancer. The aim of this study was to evaluate the ET-1 system transcriptional alterations and g-H2AX in lung tissue of Zucker rats subdivided into obese (O, n = 22) and controls (CO, n = 18) rats: under either fasting conditions (CO fc -O fc ) or acute hyperglycemia (CO AH -O AH ). Significantly higher prepro-ET-1 ( p = 0.05) and ET-converting enzyme (ECE)-2 mRNA expression was observed in O with respect to CO. A significant positive association was observed between prepro-ET-1 and ET-A in the whole rat population ( p = 0.009) or in the obese group alone ( p = 0.007). The levels of g-H2AX in O and in O AH rats were significantly higher ( p = 0.019) than in the corresponding CO and CO AH rats ( p = 0.038). The study shows an inappropriate secretion of ET-1 in O animals with a parallel DNA damage in their lungs, providing novel mechanisms by which ET receptor antagonist may exert organ protection.

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“…Total RNA was isolated according to the modified method as previously described (Chomczynski & Sacchi 1987) using Trizol reagent (Life Technologies, MD, USA) and dissolved in DEPC-treated water for direct use or stored in 70% ethanol at 70 C. Semiquantitative RT-PCR was performed to assess mRNA expression. The PCR primers used were an oligo (dT) first-strand primer and two pairs of specific primers based on previously reported sequences: 5 -TTGCACCATGG CGGACGCCTTT-3 and 5 -AGTGACGGGGCAGC CAGGTCACGCCTCCTT-3 for muscle FABP (Van Nieuwenhoven et al 1994), and 5 -CTGATCCACA TCTGCTGGAAGGTGG-3 and 5 -ACCTTCAACAC CCCAGCCATGTACG-3 for -actin (Wu et al 2000) as a housekeeping gene and internal control. The PCR product from an RNA template was obtained with Ready-To-Go RT-PCR Beads (Amersham Pharmacia Biotech, Tokyo, Japan) containing Moloney murine leukemia virus reverse transcriptase and Taq DNA polymerase.…”

Section: Rna Extraction and Analysismentioning

confidence: 99%

Fenofibrate improves insulin sensitivity in connection with intramuscular lipid content, muscle fatty acid-binding protein, and beta-oxidation in skeletal muscle

Furuhashi¹,

Ura²,

Murakami³

et al. 2002

Journal of Endocrinology

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We investigated the effect of fenofibrate, a peroxisome proliferator-activated receptor-agonist, on insulin sensitivity including lipid metabolism in skeletal muscle. Six-week-old male Sprague-Dawley rats were divided into two groups: those fed a standard chow (control) or a fructose-rich chow (fructose-fed rats (FFRs)) for 6 weeks. FFRs were treated either with a vehicle or with 30 mg/kg per day of fenofibrate for the last 2 weeks. Insulin sensitivity (M-value) was estimated by the euglycemic hyperinsulinemic glucose clamp method. Fatty acidbinding protein (FABP) in skeletal muscle was measured by ELISA, and the expression of FABP mRNA was analyzed by semi-quantitative RT-PCR. The serum and muscle triglyceride (sTG and mTG) levels and the activity of 3-hydroxyacyl-CoA dehydrogenase (HADH), a -oxidation enzyme, in muscle were also determined. FFRs showed a lower M-value and higher blood pressure, sTG and mTG than did the control group. The mTG was correlated positively with sTG and negatively with the M-value. Fenofibrate treatment for 2 weeks did not change blood pressure but significantly improved the M-value, sTG and mTG. FABP content and mRNA in the soleus muscle were significantly elevated in FFRs compared with those in the control group. Fenofibrate treatment further increased FABP. The HADH activity was comparable between the control group and FFRs, but significantly increased by fenofibrate treatment. These results suggest that fenofibrate improves insulin sensitivity not only by lowering serum lipids and subsequent influx of fatty acids into muscles but also by reducing intramuscular lipid content via further induction of FABP and stimulation of -oxidation in muscles.

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Altered paracrine effect of endothelin in blood vessels of the hyperinsulinemic, insulin resistant obese Zucker rat

Cited by 52 publications

References 26 publications

Endothelin Contributes to Basal Vascular Tone and Endothelial Dysfunction in Human Obesity and Type 2 Diabetes

Endothelin Contributes to Basal Vascular Tone and Endothelial Dysfunction in Human Obesity and Type 2 Diabetes

Transcriptional Alterations of ET-1 Axis and DNA Damage in Lung Tissue of a Rat Obesity Model

Fenofibrate improves insulin sensitivity in connection with intramuscular lipid content, muscle fatty acid-binding protein, and beta-oxidation in skeletal muscle

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