Dataset Information

Plasma C1q/TNF-Related Protein-9 Levels Are Associated with Atherosclerosis in Patients with Type 2 Diabetes without Renal Dysfunction.

ABSTRACT: Aim. C1q/tumor necrosis factor-related protein-9 (CTRP9), a paralog of adiponectin, is expressed in adipose tissue. CTRP9 exerts protective effects against obesity and atherosclerosis in rodents. We investigated the association between plasma CTRP9 levels and atherosclerosis in patients with type 2 diabetes. Methods. We included 419 patients with type 2 diabetes, 161 of whom had chronic kidney disease (CKD). Fasting plasma CTRP9 and total adiponectin levels were measured with enzyme-linked immunosorbent assay. The intima-media thickness (IMT) of the common carotid artery was measured with ultrasonography. Results. Plasma CTRP9 levels were higher in the CKD group than in the non-CKD group. Plasma CTRP9 levels were positively correlated with carotid IMT in the non-CKD group. Multivariate analyses revealed that plasma CTRP9 levels were positively associated with carotid IMT in the non-CKD group, independent of age, sex, body mass index, adiponectin, and other cardiovascular risk factors. However, plasma CTRP9 levels were not associated with carotid IMT in the CKD group. Conclusion. Plasma CTRP9 levels are associated with atherosclerosis in diabetic patients without CKD, independently of obesity, adiponectin, and traditional cardiovascular risk factors. This study indicates a potential role of CTRP9 in atherosclerosis progression in human type 2 diabetes.

SUBMITTER: Asada M

PROVIDER: S-EPMC5192323 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Plasma C1q/TNF-Related Protein-9 Levels Are Associated with Atherosclerosis in Patients with Type 2 Diabetes without Renal Dysfunction.

Asada Mariko M Morioka Tomoaki T Yamazaki Yuko Y Kakutani Yoshinori Y Kawarabayashi Reina R Motoyama Koka K Mori Katsuhito K Fukumoto Shinya S Shioi Atsushi A Shoji Tetsuo T Emoto Masanori M Inaba Masaaki M

Journal of diabetes research 20161214

<i>Aim.</i> C1q/tumor necrosis factor-related protein-9 (CTRP9), a paralog of adiponectin, is expressed in adipose tissue. CTRP9 exerts protective effects against obesity and atherosclerosis in rodents. We investigated the association between plasma CTRP9 levels and atherosclerosis in patients with type 2 diabetes. <i>Methods.</i> We included 419 patients with type 2 diabetes, 161 of whom had chronic kidney disease (CKD). Fasting plasma CTRP9 and total adiponectin levels were measured with enzym ...[more]

PMID: 28070523

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Project description:ObjectiveProgranulin and C1q/TNF-related protein-3 (CTRP3) were recently discovered as novel adipokines which may link obesity with altered regulation of glucose metabolism, chronic inflammation and insulin resistance.Research design and methodsWe examined circulating progranulin and CTRP3 concentrations in 127 subjects with (n?=?44) or without metabolic syndrome (n?=?83). Furthermore, we evaluated the relationship of progranulin and CTRP3 levels with inflammatory markers and cardiometabolic risk factors, including high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), estimated glomerular filtration rate (eGFR), and adiponectin serum concentrations, as well as carotid intima-media thickness (CIMT).ResultsCirculating progranulin levels are significantly related with inflammatory markers, hsCRP (r?=?0.30, P?=?0.001) and IL-6 (r?=?0.30, P?=?0.001), whereas CTRP3 concentrations exhibit a significant association with cardiometabolic risk factors, including waist circumference (r?=?-0.21), diastolic blood pressure (r?=?-0.21), fasting glucose (r?=?-0.20), triglyceride (r?=?-0.34), total cholesterol (r?=?-0.25), eGFR (r?=?0.39) and adiponectin (r?=?0.26) levels. Serum progranulin concentrations were higher in patients with metabolic syndrome than those of the control group (199.55 [179.33, 215.53] vs. 185.10 [160.30, 204.90], P?=?0.051) and the number of metabolic syndrome components had a significant positive correlation with progranulin levels (r?=?0.227, P?=?0.010). In multiple regression analysis, IL-6 and triglyceride levels were significant predictors of serum progranulin levels (R(2)?=?0.251). Furthermore, serum progranulin level was an independent predictor for increased CIMT in subjects without metabolic syndrome after adjusting for other cardiovascular risk factors (R(2)?=?0.365).ConclusionsSerum progranulin levels are significantly associated with systemic inflammatory markers and were an independent predictor for atherosclerosis in subjects without metabolic syndrome.Trial registrationClinicalTrials.gov NCT01668888.

Project description:ObjectiveDysregulated adipokine profiles contribute to the pathogenesis of diabetic cardiovascular complications. Endothelial cell (EC) dysfunction, a common pathological alteration in cardiovascular disorders, is exaggerated in diabetes. However, it is unclear whether and how dysregulated adipokines may contribute to diabetic EC dysfunction.Methods and resultsSerum C1q/TNF-Related Protein 5 (CTRP5) were determined in control/diabetes patients, and control/diabetic mice (high-fat diet, HFD). We observed for the first time that serum total CTRP5 was increased, high molecular weight (HMW) form was decreased, but the globular form (gCTRP5) was significantly increased in diabetic patients. These pathological alterations were reproduced in diabetic mice. To determine the pathological significance of increased gCTRP5 in diabetes, in vivo, ex vivo and in vitro experiments were performed. Diabetic atherosclerosis and EC dysfunction were significantly attenuated by the in vivo administration of CTRP5 neutralization antibody (CTRP5Ab). EC apoptosis was significantly increased in diabetic EC (isolated from HFD animal aorta) or high glucose high lipid (HGHL) cultured HUVECs. These pathological alterations were further potentiated by gCTRP5 and attenuated by CTRP5Ab. Pathway specific discovery-driven approach revealed that Nox1 expression was one of the signaling molecules commonly activated by HFD, HGHL, and gCTRP5. Treatment with CTRP5Ab reversed HFD-induced Nox1 upregulation. Finally, Nox1siRNA was used to determine the causative role of Nox1 in gCTRP5 induced EC apoptosis in diabetes. Results showed that gCTRP5 activated the mitochondrial apoptotic signal of EC in diabetes, which was blocked by the silencing Nox1 gene.ConclusionWe demonstrated for the first time that gCTRP5 is a novel molecule contributing to diabetic vascular EC dysfunction through Nox1-mediated mitochondrial apoptosis, suggesting that interventions blocking gCTRP5 may protect diabetic EC function, ultimately attenuate diabetic cardiovascular complications.

Project description:Hyperglycemia-induced endothelial cell senescence has been widely reported to be involved in the pathogenesis of type 2 diabetes mellitus‒accelerated atherosclerosis. Thus, understanding the underlying mechanisms and identifying potential therapeutic targets for endothelial cell senescence are valuable for attenuating atherosclerosis progression. C1q/tumor necrosis factor-related protein 9 (CTRP9), an emerging potential cardiokine, exerts a significant protective effect with respect to atherosclerosis, particularly in endothelial cells. However, the exact mechanism by which CTRP9 prevents endothelial cells from hyperglycemia-induced senescence remains unclear. This study aimed to investigate the effects of CTRP9 on hyperglycemia-induced endothelial cell senescence and atherosclerotic plaque formation in diabetic apolipoprotein E knockout (ApoE KO) mice. Human umbilical vein endothelial cells (HUVECs) were cultured in normal glucose (5.5 mM) and high glucose (40 mM) with or without recombinant human CTRP9 protein (3 μg/ml) for 48 h. Purified lentiviruses overexpressing CTRP9 (Lv-CTRP9) and control vectors containing green fluorescent protein (Lv-GFP) were injected via the tail vein into streptozotocin-induced diabetic ApoE KO mice. Results revealed that exposure of HUVECs to HG significantly increased the expression of Krüppel-like factor 4 (KLF4) and cyclin-dependent kinase inhibitor p21 (p21) and decreased that of telomerase reverse transcriptase (TERT). Treatment with recombinant human CTRP9 protein protected HUVECs from HG-induced premature senescence and dysfunction. CTRP9 promoted the phosphorylation of AMP-activated kinase (AMPK), attenuated the expression of KLF4 and p21 induced by HG, and increased the expression of TERT in HUVECs. Furthermore, in the background of AMPKα knockdown or KLF4 activation, the protective effects of CTRP9 were abolished. In-vivo experiments showed that the overexpression of CTRP9 inhibited vascular senescence and reduced atherosclerotic plaque formation in ApoE KO mice with diabetes. In conclusion, we demonstrate that KLF4 upregulation plays a crucial role in HG-induced endothelial senescence. This anti-atherosclerotic effect of CTRP9 may be partly attributed to the inhibition of HG-induced endothelial senescence through an AMPKα/KLF4-dependent mechanism, suggesting that CTRP9 could benefit further therapeutic approaches for type 2 diabetes mellitus‒accelerated atherosclerosis.

Dataset Information

Plasma C1q/TNF-Related Protein-9 Levels Are Associated with Atherosclerosis in Patients with Type 2 Diabetes without Renal Dysfunction.

Publications

Plasma C1q/TNF-Related Protein-9 Levels Are Associated with Atherosclerosis in Patients with Type 2 Diabetes without Renal Dysfunction.

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