Hepatic protein tyrosine phosphatase 1B (PTP1B) deficiency protects against obesity-induced endothelial dysfunction

Acknowledgments This work was supported by a Diabetes UK project grant to Dr M. Delibegović (BDARD08/0003597), Tenovus Scotland grant to Dr. M. Delibegovic and Dr. A. Agouni and travel grants from the Physiological Society and Company of Biologists to Dr. A. Agouni. Dr Delibegovic is also funded by an RCUK Fellowship, British Heart Foundation, EFSD/Lilly diabetes programme grant and the Royal Society. Dr Agouni is funded by the Royal Society and the Physiological Society. This work is supported by the INSERM and CHU of Angers. The authors are thankful to the functional imaging center of Angers (CIFAB) for the use of echocardiography.Peer reviewedPostprin

Propionyl-L-carnitine corrects metabolic and cardiovascular alterations in diet-induced obese mice and improves liver respiratory chain activity

Aims: Obesity is a primary contributor to acquired insulin resistance leading to the development of type 2 diabetes and cardiovascular alterations. The carnitine derivate, propionyl-L-carnitine (PLC), plays a key role in energy control. Our aim was to evaluate metabolic and cardiovascular effects of PLC in diet-induced obese mice. Methods: C57BL/6 mice were fed a high-fat diet for 9 weeks and then divided into two groups, receiving either free- (vehicle-HF) or PLC-supplemented water (200 mg/kg/day) during 4 additional weeks. Standard diet-fed animals were used as lean controls (vehicle-ST). Body weight and food intake were monitored. Glucose and insulin tolerance tests were assessed, as well as the HOMAIR, the serum lipid profile, the hepatic and muscular mitochondrial activity and the tissue nitric oxide (NO) liberation. Systolic blood pressure, cardiac and endothelial functions were also evaluated. Results: Vehicle-HF displayed a greater increase of body weight compared to vehicle-ST that was completely reversed by PLC treatment without affecting food intake. PLC improved the insulin-resistant state and reversed the increased total cholesterol but not the increase in free fatty acid, triglyceride and HDL/LDL ratio induced by high-fat diet. Vehicle-HF exhibited a reduced cardiac output/body weight ratio, endothelial dysfunction and tissue decrease of NO production, all of them being improved by PLC treatment. Finally, the decrease of hepatic mitochondrial activity by high-fat diet was reversed by PLC. Conclusions: Oral administration of PLC improves the insulin-resistant state developed by obese animals and decreases the cardiovascular risk associated to this metabolic alteration probably via correction of mitochondrial function

Effectiveness of pure argon for renal transplant preservation in a preclinical pig model of heterotopic autotransplantation

International audienceBackground: In kidney transplantation, the conditions of organ preservation following removal influence function recovery. Current static preservation procedures are generally based on immersion in a cold‑storage solution used under atmospheric air (approximately 78 kPa N2, 21 kPa O2, 1 kPa Ar). Research on static cold‑preservation solutions has stalled, and modifying the gas composition of the storage medium for improving preservation was considered. Organoprotective strategies successfully used noble gases and we addressed here the effects of argon and xenon on graft preservation in an established preclinical pig model of autotransplantation. Methods: The preservation solution Celsior saturated with pure argon (Argon‑Celsior) or xenon (Xenon‑Celsior) at atmospheric pressure was tested versus Celsior saturated with atmospheric air (Air‑Celsior). The left kidney was removed, and Air‑Celsior (n = 8 pigs), Argon‑Celsior (n = 8) or Xenon‑Celsior (n = 6) was used at 4 °C to flush and store the transplant for 30 h, a duration that induced ischemic injury in our model when Air‑Celsior was used. Hetero‑ topic autotransplantation and contralateral nephrectomy were performed. Animals were followed for 21 days. Results: The use of Argon‑Celsior vs. Air‑Celsior: (1) improved function recovery as monitored via creatinine clear‑ ance, the fraction of excreted sodium and tubulopathy duration; (2) enabled diuresis recovery 2–3 days earlier; (3) improved survival (7/8 vs. 3/8 pigs survived at postoperative day‑21); (4) decreased tubular necrosis, interstitial fibrosis, apoptosis and inflammation, and preserved tissue structures as observed after the natural death/euthanasia; (5) stimulated plasma antioxidant defences during the days following transplantation as shown by monitoring the " reduced ascorbic acid/thiobarbituric acid reactive substances " ratio and Hsp27 expression; (6) limited the inflamma‑ tory response as shown by expression of TNF‑alpha, IL1‑beta and IL6 as observed after the natural death/euthanasia. Conversely, Xenon‑Celsior was detrimental, no animal surviving by day‑8 in a context where functional recovery, renal tissue properties and the antioxidant and inflammation responses were significantly altered. Thus, the positive effects of argon were not attributable to the noble gases as a group. Conclusions: The saturation of Celsior with argon improved early functional recovery, graft quality and survival. Manipulating the gas composition of a preservation medium constitutes therefore a promising approach to improve preservation

Estrogen Receptor Alpha as a Key Target of Red Wine Polyphenols Action on the Endothelium

BACKGROUND: A greater reduction in cardiovascular risk and vascular protection associated with diet rich in polyphenols are generally accepted; however, the molecular targets for polyphenols effects remain unknown. Meanwhile evidences in the literature have enlightened, not only structural similarities between estrogens and polyphenols known as phytoestrogens, but also in their vascular effects. We hypothesized that alpha isoform of estrogen receptor (ERalpha) could be involved in the transduction of the vascular benefits of polyphenols. METHODOLOGY/PRINCIPAL FINDINGS: Here, we used ERalpha deficient mice to show that endothelium-dependent vasorelaxation induced either by red wine polyphenol extract, Provinols, or delphinidin, an anthocyanin that possesses similar pharmacological profile, is mediated by ERalpha. Indeed, Provinols, delphinidin and ERalpha agonists, 17-beta-estradiol and PPT, are able to induce endothelial vasodilatation in aorta from ERalpha Wild-Type but not from Knock-Out mice, by activation of nitric oxide (NO) pathway in endothelial cells. Besides, silencing the effects of ERalpha completely prevented the effects of Provinols and delphinidin to activate NO pathway (Src, ERK 1/2, eNOS, caveolin-1) leading to NO production. Furthermore, direct interaction between delphinidin and ERalpha activator site is demonstrated using both binding assay and docking. Most interestingly, the ability of short term oral administration of Provinols to decrease response to serotonin and to enhance sensitivity of the endothelium-dependent relaxation to acetylcholine, associated with concomitant increased NO production and decreased superoxide anions, was completely blunted in ERalpha deficient mice. CONCLUSIONS/SIGNIFICANCE: This study provides evidence that red wine polyphenols, especially delphinidin, exert their endothelial benefits via ERalpha activation. It is a major breakthrough bringing new insights of the potential therapeutic of polyphenols against cardiovascular pathologies

Rôle du récepteur aux œstrogènes dans la cardio et la vasculo-protection induites par les polyphénols du vin rouge

ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Red wine polyphenol compounds favor neovascularisation through estrogen receptor α-independent mechanism in mice.

Red wine polyphenol compounds (RWPC) exert paradoxical effects depending on the dose on post-ischemic neovascularisation. Low dose RWPC (0.2 mg/kg/day) is pro-angiogenic, whereas high dose (20 mg/kg/day) is anti-angiogenic. We recently reported that the endothelial effect of RWPC is mediated through the activation of a redox-sensitive pathway, mitochondrial biogenesis and the activation of α isoform of the estrogen receptor (ERα). Here, we investigated the implication of ERα on angiogenic properties of RWPC. Using ovariectomized mice lacking ERα treated with high dose of RWPC after hindlimb ischemia, we examined blood flow reperfusion, vascular density, nitric oxide (NO) production, expression and activation of proteins involved in angiogenic process and muscle energy sensing network. As expected, high dose of RWPC treatment reduced both blood flow and vascular density in muscles of mice expressing ERα. These effects were associated with reduced NO production resulting from diminished activity of eNOS. In the absence of RWPC, ERα deficient mice showed a reduced neo-vascularisation associated with a decreased NO production. Surprisingly in mice lacking ERα, high dose of RWPC increased blood flow and capillary density in conjunction with increased NO pathway and production as well as VEGF expression. Of particular interest is the activation of Sirt-1, AMPKα and PGC-1α/β axis in ischemic hindlimb from both strains. Altogether, the results highlight a pro-angiogenic property of RWPC via an ERα-independent mechanism that is associated with an up-regulation of energy sensing network. This study brings a corner stone of a novel pathway for RWPC to correct cardiovascular diseases associated with failed neovascularisation

How Sublaminar Bands Affect Postoperative Sagittal Alignment in AIS Patients with Preoperative Hypokyphosis? Results of a Series of 34 Patients with 2-Year Follow-Up

Hypokyphosis is currently observed in thoracic idiopathic scoliosis. The use of sublaminar bands allows a good restoration of sagittal balance of the spine. The aim of the study was to provide a middle-term radiographic analysis of patients with adolescent idiopathic scoliosis with preoperative hypokyphosis treated by posterior arthrodesis with sublaminar bands. This retrospective study included 34 patients with Lenke 1 scoliosis associated with hypokyphosis (TK < 20°). A radiographic evaluation was performed with a 2-year follow-up. Cobb angle, cervical lordosis, thoracic kyphosis, lumbar lordosis, and pelvic parameters were measured preoperatively, postoperatively, and at 6-month and 2-year follow-up. The mean preoperative thoracic kyphosis was 10.5° versus 24.1° postoperatively (p<0.001), representing a mean gain of 13°. Cobb angle ranged from 59.3° to 17.9° postoperatively (mean correction 69%, p<0.001). Cobb angle increased between the immediate postoperative measurement and the 6-month follow-up (17.9 versus 19.9, p=0.03). Cervical curvature changed from a 5.6° kyphosis to a 3.5° lordosis (p=0.001). Concerning lumbar lordosis, preoperative measurement was 39.7° versus 41.3° postoperatively (p=0.27). At 6-month follow-up, lumbar lordosis significantly increased to 43.6° (p=0.03). All parameters were stable at final follow-up. Correction performed by sublaminar bands is efficient for both fontal and sagittal planes. Moreover, the restoration of normal thoracic kyphosis is followed by an adaptation of the adjacent curvatures with improved cervical lordosis and lumbar lordosis

Evaluation of the protein expression levels extracted from the right (non ischemic) gastrocnemius and soleus muscles in ovarectomised (OVX) ERα WT and KO mice treated or not with 20 mg/kg of RWPC for 28 days.

<p>Representative images of blots showing protein expression levels in non ischemic leg muscle (a) Quantification of protein expressions expressed normalized to β-actin expression, (b) (mean ± SEM) (n = 5). <i>*P<0.05,</i> **<i>P<0.01, ***P<0.001 vs. control group; ##P<0.01; ###P<0.001 vs control OVX KO; ¤P<0.05, ¤¤P<0.01, ¤¤¤P<0.001 vs OVX WT treated.</i></p