المؤلفون: do Nascimento, Thiago Bruder, Kennard, Simone, Nathaniel, Taylor, Antonova, Galina, de Chantemele, Eric J Belin

المصدر: The FASEB Journal ; volume 33, issue S1 ; ISSN 0892-6638 1530-6860

الوصف: Highly active antiretroviral therapy (HAART) has been used at suppressing HIV replication, as a side effect HAART promotes lipodystrophy, which is a metabolic disorder characterized by an abnormal adipose tissue distribution, reduced leptin plasma levels and vascular complications. Leptin replacement therapy (LRT) is currently used to treat metabolic dysfunctions in patients diagnosed with congenital lipodystrophy. Here, we sought to investigate whether LRT restores vascular function and reduces inflammation in mice treated with the antiretroviral agent, ritonavir. Four weeks of ritonavir reduced body weight [control (C): 28.4±0.5 vs. Rit: 24.4 ± 0.2g*, *P<0.05], fat mass (C: 10 ± 0.4 vs. Rit: 4.5 ± 0.9 %*, *P<0.05) and leptin plasma levels (C: 4.7 ± 0.05 vs. Rit: 2.0 ± 0.36 ng/mL*, *P<0.05) confirming that it induces acquired lipodystrophy. Acquired lipodystrophy impaired endothelial function, increased plasma lipid peroxidation and vascular H 2 O 2, and ROS producing enzymes (Nox1 and NoxA1). Furthermore, acquired lipodystrophy was associated with vascular inflammation characterized by elevation of NLRP3, Caspase‐1, IL‐1β, MCP‐1, F4/80, CCR5 and CCL5 gene expression. ROS scavenging via tempol (SOD mimetic, 100 μmol/l) or GKT771 (Nox1 inhibitor, 10 μmol/l) restored endothelial function. LRT (10μg/day/7 days, osmotic mini‐pump), at the end of the 3‐week ritonavir, restored endothelial function, reduced vascular oxidative stress and Nox1 and NOXA1 gene expression and vascular inflammation. Nox1 deficiency (Nox1−/−) protected mice from acquired lipodystrophy‐induced endothelial dysfunction and reduced inflammatory markers including CCR5 and CCL5. In order to analyze whether vascular inflammation is occurring via CCR5/CCL5, we induced lipodystrophy in CCR5 deficient mice (CCR5−/−). These mice were protected from acquired lipodystrophy‐induced endothelial dysfunction and vascular inflammation. Moreover, deleting endothelial leptin signaling via specific deletion of leptin receptor (LepR) in endothelial ...

الإتاحة: https://doi.org/10.1096/fasebj.2019.33.1_supplement.836.9Test

المؤلفون: Hong Shi, Goo, Brandee, Kim, David, Kress, Taylor C., Ogbi, Mourad, Mintz, James, Hanping Wu, de Chantemèle, Eric J. Belin, Stepp, David, Xiaochun Long, Guha, Avirup, Lee, Richard, Carbone, Laura, Annex, Brian H., Hui, David Y., Ha Won Kim, Weintraub, Neal L.

المصدر: Frontiers in Immunology; 3/16/2023, Vol. 14, p1-12, 12p

مصطلحات موضوعية: ADIPOSE tissues, BIOMARKERS, SYSTEMIC lupus erythematosus, THORACIC aorta, ARTERIAL calcification

مستخلص: Introduction: Patients with systemic lupus erythematosus (SLE) are at elevated risk for Q10 cardiovascular disease (CVD) due to accelerated atherosclerosis. Compared to heathy control subjects, lupus patients have higher volumes and densities of thoracic aortic perivascular adipose tissue (PVAT), which independently associates with vascular calcification, a marker of subclinical atherosclerosis. However, the biological and functional role of PVAT in SLE has not been directly investigated. Methods: Using mouse models of lupus, we studied the phenotype and function of PVAT, and the mechanisms linking PVAT and vascular dysfunction in lupus disease. Results and discussion: Lupus mice were hypermetabolic and exhibited partial lipodystrophy, with sparing of thoracic aortic PVAT. Using wire myography, we found that mice with active lupus exhibited impaired endothelium-dependent relaxation of thoracic aorta, which was further exacerbated in the presence of thoracic aortic PVAT. Interestingly, PVAT from lupus mice exhibited phenotypic switching, as evidenced by "whitening" and hypertrophy of perivascular adipocytes along with immune cell infiltration, in association with adventitial hyperplasia. In addition, expression of UCP1, a brown/beige adipose marker, was dramatically decreased, while CD45-positive leukocyte infiltration was increased, in PVAT from lupus mice. Furthermore, PVAT from lupus mice exhibited a marked decrease in adipogenic gene expression, concomitant with increased pro-inflammatory adipocytokine and leukocyte marker expression. Taken together, these results suggest that dysfunctional, inflamed PVAT may contribute to vascular disease in lupus. [ABSTRACT FROM AUTHOR]

: Copyright of Frontiers in Immunology is the property of Frontiers Media S.A. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Stepp, David W., Osakwe, Christabell C., de Chantemele, Eric J. Belin, Mintz, James D.

المساهمون: Diabetes and Obesity Discovery Institute Flexcore and Scholar Program

المصدر: Physiological Reports ; volume 1, issue 6, page e00146 ; ISSN 2051-817X

الإتاحة: https://doi.org/10.1002/phy2.146Test

المؤلفون: Norman, Joseph Blake, Herren, David, Tremblay, Michel L, Stepp, David W, de Chantemele, Eric J Belin

المصدر: The FASEB Journal ; volume 26, issue S1 ; ISSN 0892-6638 1530-6860

الوصف: Impaired vascular function is a common feature in type I diabetic patients. PTP1B deletion prevents endothelial dysfunction and leptin infusion restores cardiovascular dysfunction induced by type I diabetes. We hypothesized that increasing leptin sensitivity via PTP1B deletion prevents vascular dysfunction in type I diabetic mice. Type I diabetes was induced with streptozotocin (STZ) in male and female Balb/C and PTP1B KO mice. Vascular function was studied after 24 days of STZ on aortic rings mounted on a wire myograph. Glycemia was significantly increased with STZ and further exaggerated by PTP1B deletion in male mice only (Balb/CMSTZ: 342±18 vs PTP1BMSTZ: 509±26 mg/dl, p<0.05). Endothelial function assessed via acetylcholine (ACh)‐mediated relaxation was reduced in both male and female Balb/C mice but preserved in PTP1B KO animals. While LNAME completely abolished ACh‐mediated relaxation in Balb/C mice, addition of indomethacin was required to abolish relaxation in PTP1B KO mice treated with STZ, suggesting dilatory cyclooxygenase derivatives involvement. Phenylephrine (PE)‐induced constriction was increased by STZ in male and female Balb/C, but preserved in PTP1B KO male mice only. Taken together these data indicate that PTP1B deletion protects against the harmful vascular effects of type I diabetes, independent of hyperglycemia and with more pronounced effects in male than female mice.

الإتاحة: https://doi.org/10.1096/fasebj.26.1_supplement.866.18Test

المؤلفون: de Chantemele, Eric J Belin

المصدر: The FASEB Journal ; volume 26, issue S1 ; ISSN 0892-6638 1530-6860

الوصف: Besides inducing sympatho‐activation, leptin promotes T cell‐mediated pro‐inflammatory cytokines release. Since T cells play a key role in hypertension we hypothesized that increasing leptin sensitivity via protein tyrosine phosphatase 1B (PTP1B) deletion or increasing leptin concentration would promote inflammation and hypertension through a T cell dependent mechanism. PTP1B was deleted in mice on either a TH1 (C57) or a TH2 (Balb/C) T cell background. Blood pressure (BP) recording showed that PTP1B deletion and leptin infusion elevated BP in TH2 responsive mice only. As reflected by the BP response to ganglionic blockade, sympathetic tone was increased in response to PTP1B deletion and leptin in TH2 mice. Plasma aldosterone levels, indexes of the activation of the renin‐angiotensin‐aldosterone system were also increased in response to leptin and PTP1B deletion in TH2 mice. PTP1B deletion suppressed TH2‐derived anti‐inflammatory cytokine secretion (IL‐10, IL‐4) and increased TH1‐derived inflammatory cytokines (IL‐6, TNFα) production in TH2 mice. IL‐10 and TNFα secretion were not affected by PTP1B deletion in mice on TH1 responder background but levels of TH1 derived pro‐inflammatory cytokines (IL‐6, INFγ) were reduced. Taken together these data suggest that T cell background might influence BP response to leptin likely by controlling the inflammatory response to leptin.

الإتاحة: https://doi.org/10.1096/fasebj.26.1_supplement.1128.6Test

المؤلفون: de Chantemèle, Eric J. Belin, Ali, Mohammed Irfan, Mintz, James D., Rainey, William E., Tremblay, Michel L., Fulton, David J., Stepp, David W.

المصدر: Hypertension ; volume 60, issue 5, page 1273-1279 ; ISSN 0194-911X 1524-4563

الوصف: Obesity is a major risk factor for hypertension. The copresentation of hypertension and insulin resistance (IR) suggests a role for IR in blood pressure (BP) dysregulation. To test this hypothesis, peripheral IR has been genetically subtracted in a model of obesity by crossing leptin receptor mutant mice (K db H PTP ) with mice lacking protein tyrosine phosphatase 1B (insulin desensitizer, H db K PTP ) to generate obese insulin-sensitive mice (K db K PTP ). BP was recorded in lean (H db H PTP , H db K PTP ) and obese (K db H PTP , K db K PTP ) mice via telemetry, and a frequency analysis of the recording was performed to determine BP variability. Correction of IR in obese mice normalized BP values to baseline levels (H db H PTP : 116±2 mm Hg; K db H PTP : 129±4 mm Hg; K db K PTP : 114±5 mm Hg) and restored BP variability by decreasing its standard deviation and the frequency of BP values over the upper autoregulatory limit of the kidneys. However, although IR-induced increases in proteinuria (versus 53±13 μg/d, H db H PTP ) were corrected in K db K PTP (112±39 versus 422±159 μg/d, K db H PTP ), glomerular hypertrophy was not. IR reduced plasma aldosterone levels ruling out a role for mineralocorticoids in the development of hypertension. Taken together, these data indicate that correction of IR prevents hypertension, BP variability, and microalbuminuria in obese mice. Although the mechanism remains to be fully determined, increases in aldosterone or sympathoactivation of the cardiovascular system seem to be less likely contributors.

الإتاحة: https://doi.org/10.1161/hypertensionaha.112.196295Test

المؤلفون: de Chantemèle, Eric J. Belin, Vessières, Emilie, Guihot, Anne-Laure, Toutain, Bertrand, Maquignau, Maud, Loufrani, Laurent, Henrion, Daniel

مصطلحات موضوعية: Original Article

الوصف: Aims Endothelial dysfunction in resistance arteries (RAs) leads to end-organ damage in type 2 diabetes. Remodelling of RAs in response to chronic increases in blood flow depends on the integrity of the endothelium. Since type 2 diabetes impairs endothelial sensitivity to flow and increases oxidative stress, we hypothesized that flow-induced remodelling in RAs would be impaired in diabetes. Thus, we studied the structural and functional adaptation of RAs from Zucker diabetic fatty (ZDF) and lean Zucker (LZ) rats to chronic changes in flow. Methods and results Mesenteric RAs were alternatively ligated so that one artery was submitted to high flow (HF) and compared with normal-flow (NF) arteries located at distance. After 3 weeks, arteries were studied in vitro ( n = 10 rats per group). Arterial diameter (468 vs. 394 ± 8 µm) and endothelial (acetylcholine)-dependent dilation (91 ± 8 vs. 75 ± 6% dilation) were higher in HF than in NF arteries in LZ rats. In ZDF rats, diameter (396 ± 9 vs. 440 ± 17 µm) and acetylcholine-mediated dilation (42 ± 8 vs. 75 ± 7%) were lower in HF than in NF arteries. Nevertheless, endothelial NO synthase and NADP(H) oxidase subunits (gp91, p67) expression level and superoxide production (dihydroethidium staining) were higher in HF than in NF arteries in both strains, suggesting an efficient flow-sensing process in ZDF rats. In ZDF rats, basal oxidative stress was higher compared with LZ rats: dihydroethidium staining was higher in NF and HF arteries from ZDF rats, and acetylcholine-mediated dilation was improved by an acute antioxidant (tempol) in NF and HF arteries from ZDF rats. Thus, superoxide overproduction in ZDF rats impaired NO-dependent dilation and HF remodelling. Indeed, a chronic treatment with tempol increased HF artery diameter and endothelium-dependent dilation in ZDF rats. Conclusion In type 2 diabetic rats, a chronic increase in blood flow failed to induce outward remodelling and to improve endothelium-dependent dilation, mainly because of superoxide overproduction.

وصف الملف: text/html

العلاقة: http://cardiovascres.oxfordjournals.org/cgi/content/short/cvn334v2Test; http://dx.doi.org/10.1093/cvr/cvn334Test

الإتاحة: https://doi.org/10.1093/cvr/cvn334Test
http://cardiovascres.oxfordjournals.org/cgi/content/short/cvn334v2Test

المؤلفون: Faulkner, Jessica L., Harwood, Daisy, Kennard, Simone, Antonova, Galina, Clere, Nicolas, de Chantemèle, Eric J. Belin

المصدر: American Journal of Physiology: Heart & Circulatory Physiology; Jan2021, Vol. 320 Issue 1, pH211-H220, 10p

مصطلحات موضوعية: NITRIC-oxide synthases, MINERALOCORTICOID receptors, SALT-free diet, VASCULAR endothelium, WESTERN diet, DIETARY sodium

مستخلص: Recent findings from our group demonstrated that females exhibit higher endothelial mineralocorticoid receptor (MR) expression than males, which predisposes them to aldosterone-mediated endothelial dysfunction in the context of metabolic disorders. However, whether the endothelium of female mice presents a higher propensity to MR-mediated dysfunction than that of males in the absence of comorbidities remains unknown. We therefore sought to investigate whether increasing aldosterone production endogenously with sodium restriction impairs endothelial function in otherwise healthy female mice. We fed male and female Balb/C mice a normal (0.4% NaCl; NSD) or sodium-restricted diet (0.05% NaCl; SRD) for 4 wk. Females exhibited higher baseline endothelial function (relaxation to acetylcholine) and lower vascular contractility (constriction to phenylephrine, serotonin, and KCl). However, SRD impaired endothelial-dependent relaxation and increased vascular contractility in female mice, effectively ablating the baseline sex difference. Female sex also increased baseline adrenal CYP11B2 expression; however, SRD significantly enhanced CYP11B2 expression in male and female mice and ablated the sex difference. Nitric oxide synthase (NOS) inhibition with N^ɷ-nitro-L-arginine methyl ester hydrochloride eliminated both sex as well as diet-induced differences in endothelial dysfunction. In accordance, females demonstrated higher vascular endothelial NOS expression at baseline, which SRD significantly decreased. In addition, SRD diminished vascular NOX4 expression in female mice only. MR blockade with spironolactoneprotected female mice from decreases in endothelial-dependent relaxation but not increases in vascular contractility. Utilizing sodium restriction as a method to increase plasma aldosterone levels in healthy female mice, we demonstrated that female mice are more susceptible to vascular damage via MR activation in the vascular endothelium only. NEW & NOTEWORTHY Female sex confers improved endothelial relaxation and vascular constriction responses in female Balb/C mice compared with males under baseline conditions. Sodium restriction impairs endothelial function, which is nitric oxide dependent, and increases vascular contractility in association with reduced vascular endothelial nitric oxide synthase and NOX4 expression in female mice ablating the baseline sex difference. Mineralocorticoid receptor antagonism ablates sodium restriction-induced endothelial dysfunction, but not increased vascular contractility, in female mice. [ABSTRACT FROM AUTHOR]

: Copyright of American Journal of Physiology: Heart & Circulatory Physiology is the property of American Physiological Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: do Nascimento, Thiago Bruder, Kennard, Simone, Chen, Weiqin, de Chantemèle, Eric J Belin

المساهمون: American Heart Association, National Heart, Lung, and Blood Institute

المصدر: The FASEB Journal ; volume 31, issue S1 ; ISSN 0892-6638 1530-6860

الوصف: Lipodystrophy is a congenital disorder or a condition acquired later in life characterized by a total or partial absence of adipose tissue resulting in drastic reductions in leptin levels, metabolic disorders and cardiovascular disease (CVD). In 2014 the Food and Drug Administration approved the use of leptin as a therapy to minimize the metabolic dysfunction developed by lipodystrophic patients. However, whether leptin replacement therapy improves lipodystrophy‐associated CVD remains unknown. Here, we tested the hypothesis that exogenous leptin restores vascular function in lipodystrophic mice by regulating redox signaling. Studies were conducted in 10–12 week‐old male Berardinelli‐Seip gene (gBscl2−/−) deficient mice, a well‐characterized model of congenital lipodystrophy, as well as in inducible Bscl2 deficient mice (iBscl2−/−), a model of acquired lipodystrophy. Reduction of adipose tissue in gBscl2−/− and iBscl2−/− mice was confirmed by nuclear magnetic resonance spectroscopy: [wild‐type (WT): 8.1 ± 0.3 vs gBlsc2−/− 1.9 ± 0.5* and iBscl2−/−: 4.2 ± 0.7* (%)*P<0.05 vs WT]. Both gBscl2−/− and iBscl2−/− exhibit reduced plasma leptin levels, hyperglycemia, hyperinsulinemia and hyperlipidemia, indicative of metabolic dysfunction. Radio‐telemetry measurements did not report increases in blood pressure in lipodystrophic mice. Analysis of the aortic vascular reactivity via wire‐myography revealed a severe endothelial dysfunction in both gBscl2−/− and iBscl2−/−, characterized by an impaired relaxation to acetylcholine but no alteration of the endothelium‐independent relaxation (relaxation to sodium nitroprusside). Acute reactive oxygen species scavenging with the superoxide dismutase mimetic tempol (100 μmol/l) or the NOX1‐NOX4 inhibitor GKT137831 (10 μmol/l) restored endothelial function in aortic rings from both gBscl2−/− and iBscl2−/− mice. In parallel, quantitative real‐time RT‐PCR, revealed increases in Nox1 and Nox4 gene expression, as well as in the expression of the NADPH oxidase regulatory subunit NOXA1, ...

الإتاحة: https://doi.org/10.1096/fasebj.31.1_supplement.1013.2Test

المؤلفون: Bruder-Nascimento, Thiago, Kress, Taylor C., Kennard, Simone, de Chantemèle, Eric J. Belin, Belin de Chantemèle, Eric J

المصدر: Journal of the American Heart Association; 10/20/2020, Vol. 9 Issue 19, p1-25, 25p