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Adiponectin deficiency promotes endothelial activation and profoundly exacerbates sepsis-related mortality.

ABSTRACT: Sepsis is a multifactorial, and often fatal, disorder typically characterized by widespread inflammation and immune activation with resultant endothelial activation. In the present study, we postulated that the adipokine adiponectin serves as a critical modulator of survival and endothelial activation in sepsis. To this aim, we evaluated both loss-of-function (adiponectin gene-deficient mice) and subsequent gain-of-function (recombinant adiponectin reconstitution) strategies in two well-established inflammatory models, cecal ligation perforation (CLP) and thioglyocollate-induced peritonitis. Adipoq(-/-) mice, subjected to CLP, exhibited a profound ( approximately 8-fold) reduction in survival compared with their wild-type Adipoq(+/+) littermates after 48 h. Furthermore, compared with wild-type controls, thioglycollate challenge resulted in a markedly greater influx of peritoneal neutrophils in Adipoq(-/-) mice accompanied by an excess production of key chemoattractant cytokines (IL-12p70, TNFalpha, MCP-1, and IL-6) and upregulation of aortic endothelial adhesion molecule VCAM-1 and ICAM-1 expressions. Importantly, all of these effects were blunted by recombinant total adiponectin administration given 3 days prior to thioglycollate challenge. The protective effects of adiponectin were ascribed largely to higher-order adiponectin oligomers, since administration of recombinant C39A trimeric adiponectin did not attenuate endothelial adhesion molecule expression in thioglycollate-challenged Adipoq(-/-) mice. These data suggest a critical role of adiponectin as a modulator of survival and endothelial inflammation in experimental sepsis and a potential mechanistic link between adiposity and increased sepsis.

SUBMITTER: Teoh H

PROVIDER: S-EPMC2536730 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Adiponectin deficiency promotes endothelial activation and profoundly exacerbates sepsis-related mortality.

Teoh Hwee H Quan Adrian A Bang K W Annie KW Wang Guilin G Lovren Fina F Vu Vivian V Haitsma Jack J JJ Szmitko Paul E PE Al-Omran Mohammed M Wang Chao-Hung CH Gupta Milan M Peterson Mark D MD Zhang Haibo H Chan Lawrence L Freedman John J Sweeney Gary G Verma Subodh S

American journal of physiology. Endocrinology and metabolism 20080715 3

Sepsis is a multifactorial, and often fatal, disorder typically characterized by widespread inflammation and immune activation with resultant endothelial activation. In the present study, we postulated that the adipokine adiponectin serves as a critical modulator of survival and endothelial activation in sepsis. To this aim, we evaluated both loss-of-function (adiponectin gene-deficient mice) and subsequent gain-of-function (recombinant adiponectin reconstitution) strategies in two well-establis ...[more]

PMID: 18628355

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Project description:Diabetes promotes maladaptive changes in the endothelium that lead to its dysfunction and contribute to the vascular pathology of diabetes. We have previously reported the up-regulation of galectin-3, a ?-galactoside-binding lectin, in the endothelium and sera of diabetic mice, implicating this molecule in diabetic vasculopathy and suggesting its potential as a biomarker of the disease. Therefore, we sought to assess the role of galectin-3 in the vascular pathology of diabetes.Galectin-3 knockout mice (KO) and wild-type mice (WT) were fed either a high-fat diet (HFD) (60 % fat calories) to produce insulin resistant diabetes, or standard chow (12 % fat calories), and their metabolic and endothelial responses were measured. After 8 weeks, the aortic and skeletal muscle endothelia were isolated by fluorescence sorting of CD105(+)/CD45(-) cells and comprehensive transcriptional analyses were performed. Transcripts differentially dysregulated by HFD in KO endothelium compared to WT were confirmed by semi-quantitative RT-PCR, and protein expression was determined by immunofluorescence of aortic and muscle tissue. Ingenuity® Pathway Analysis was used to identify pathways up-regulated by HFD in the KO, such as the coagulation cascade, and measurements of blood clotting activity were performed to confirm these results.KO mice demonstrate greater hyperglycemia and impaired glucose tolerance but lower insulin levels on HFD compared to WT. KO mice demonstrate a more robust transcriptional response to HFD in the vascular endothelium compared to WT. Transcripts dysregulated in the KO endothelium after HFD are involved in glucose uptake and insulin signaling, vasoregulation, coagulation, and atherogenesis. One of the most down-regulated transcripts in the endothelium of the KO after HFD was the glucose transporter, Glut4/Slc2a4. GLUT4 immunofluorescence confirmed lower protein abundance in the endothelium and muscle of the HFD-fed KO. Prothrombin time was decreased in the diabetic KO indicating increased coagulation activity.Galectin-3 deficiency leads to exacerbated metabolic derangement and endothelial dysfunction. The impaired tissue uptake of glucose in KO mice can be attributed to the reduced expression of GLUT4. Enhanced coagulation activity in the diabetic KO suggests a protective role for galectin-3 against thrombosis. These studies demonstrate that galectin-3 deficiency contributes both to the pathogenesis of diabetes and the associated vasculopathy.

Project description:Loss-of-function mutations of the gene encoding Krev interaction trapped protein 1 (KRIT1) are associated with the pathogenesis of Cerebral Cavernous Malformation (CCM), a major cerebrovascular disease characterized by abnormally enlarged and leaky capillaries and affecting 0.5% of the human population. However, growing evidence demonstrates that KRIT1 is implicated in the modulation of major redox-sensitive signaling pathways and mechanisms involved in adaptive responses to oxidative stress and inflammation, suggesting that its loss-of-function mutations may have pathological effects not limited to CCM disease. The aim of this study was to address whether KRIT1 loss-of-function predisposes to the development of pathological conditions associated with enhanced endothelial cell susceptibility to oxidative stress and inflammation, such as arterial endothelial dysfunction (ED) and atherosclerosis. Silencing of KRIT1 in human aortic endothelial cells (HAECs), coronary artery endothelial cells (HCAECs), and umbilical vein endothelial cells (HUVECs) resulted in increased expression of endothelial proinflammatory adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) and in enhanced susceptibility to tumor necrosis factor alpha (TNF-?)-induced apoptosis. These effects were associated with a downregulation of Notch1 activation that could be rescued by antioxidant treatment, suggesting that they are consequent to altered intracellular redox homeostasis induced by KRIT1 loss-of-function. Furthermore, analysis of the aorta of heterozygous KRIT1+/- mice fed a high-fructose diet to induce systemic oxidative stress and inflammation demonstrated a 1.6-fold increased expression of VCAM-1 and an approximately 2-fold enhanced fat accumulation (7.5% vs 3.6%) in atherosclerosis-prone regions, including the aortic arch and aortic root, as compared to corresponding wild-type littermates. In conclusion, we found that KRIT1 deficiency promotes ED, suggesting that, besides CCM, KRIT1 may be implicated in genetic susceptibility to the development of atherosclerotic lesions.

Project description:ObjectivesNuclear factor-κB is a critical regulator of cell-survival genes and the host inflammatory response. The purpose of this study was to investigate the role of enterocyte-specific NF-kB in sepsis through selective ablation of IkB kinase.DesignProspective, randomized controlled study.SettingAnimal laboratories in university medical centers.Subjects and interventionsMice lacking functional NF-kB in their intestinal epithelium (Vil-Cre/Ikkβ) and wild-type mice were subjected to sham laparotomy or cecal ligation and puncture. Animals were killed at 24 hours or followed 7 days for survival.Measurements and main resultsSeptic wild-type mice had decreased villus length compared with sham mice, whereas villus atrophy was further exacerbated in septic Vil-Cre/Ikkβ mice. Sepsis induced an increase in intestinal epithelial apoptosis compared with sham mice, which was further exacerbated in Vil-Cre/Ikkβ mice. Sepsis induced intestinal hyperpermeability in wild-type mice compared with sham mice, which was further exacerbated in septic Vil-Cre/Ikkβ mice. This was associated with increased intestinal expression of claudin-2 in septic wild-type mice, which was further increased in septic Vil-Cre/Ikkβ mice. Both, pro-inflammatory and anti-inflammatory cytokines were increased in serum following cecal ligation and puncture, and interleukin 10 and monocyte chemoattractant protein-1 levels were higher in septic Vil-Cre/Ikkβ mice than in septic wild-type mice. All septic mice were bacteremic, but no differences in bacterial load were identified between wild-type and Vil-Cre/Ikkβ mice. To determine the functional significance of these results, animals were followed for survival. Septic wild-type mice had lower mortality than septic Vil-Cre/Ikkβ mice (47% vs 80%, p<0.05). Antitumor necrosis factor administration decreased intestinal apoptosis, permeability, and mortality in wild-type septic mice, and a similar improvement in intestinal integrity and survival were seen when antitumor necrosis factor was given to Vil-Cre/Ikkβ mice.ConclusionsEnterocyte-specific NF-kB has a beneficial role in sepsis by partially preventing sepsis-induced increases in apoptosis and permeability, which are associated with worsening mortality.

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Adiponectin deficiency promotes endothelial activation and profoundly exacerbates sepsis-related mortality.

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Adiponectin deficiency promotes endothelial activation and profoundly exacerbates sepsis-related mortality.

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