C1q/TNF-related Protein 9 Research Articles

Genetic Evidence of Causal Effect between C1q/TNF-Related Protein-1 and Atherosclerosis: a Bidirectional and Multivariate Mendelian Randomization Study.

To investigate the causal relationship between C1q/TNF-related protein-1 (CTRP1) and atherosclerosis across various vascular sites, informed by studies connecting CTRP1 to coronary artery disease. Summary statistics of CTRP1 from the available genome-wide association studies and atherosclerosis in classic vascular sites (including cerebral, coronary, and other arteries) from the FinnGen biobank were extracted for a primary MR analysis, and the analysis was replicated using Ischemic Stroke cohort (large artery atherosclerosis) for validation. The inverse variance-weighted method was used for primary assessment. Sensitivity analysis was performed by Cochrane's Q test and leave-one-out analysis. Potential pleiotropic effects were assessed by MR-Egger intercept and MR-PRESSO global test. Additionally, multivariable MR (MVMR) analysis was performed to investigate the independent effect of CTRP1 on atherosclerosis after removing confounding factors. Reliable causal evidence was found for CTRP1 involvement in three atherosclerosis endpoints: causal effects of CTRP1 on cerebral atherosclerosis (OR=1.31, CI:1.04-1.66; FDR_P=0.0222)], coronary atherosclerosis (OR=1.13, CI: 1.08-1.19; FDR_P=2.86e-07), and atherosclerosis at other sites (OR=1.06, CI:1.02-1.11; FDR_P=0.0125). The validation cohort further confirmed its causal effect on large-artery atherosclerosis (OR=1.10, CI:1.03-1.18; FDR_P=0.0115). The reverse MR analysis did not support the causal effect of atherosclerosis on CTRP1. Moreover, the MVMR analysis, adjusting for confounders (CTRP3, CTRP5, and CTRP9A), highlighted a significant independent causal effect of CTRP1 remaining on atherosclerosis. CTRP1 may represent a promising target for preventing and treating systemic atherosclerosis.

Downregulation of CTRP1 reduces radio-resistance in glioblastoma cells by inhibiting the expression of CD133 after X-ray and carbon ion irradiation

Glioblastomas (GBMs), the most prevalent primary malignant brain tumors, present significant challenges due to their invasive nature, high recurrence rates, and limited treatment options. Radiotherapy is a cornerstone in the management of GBMs; however, resistance to treatment poses a substantial obstacle. This study investigates the role of adipokine C1q/TNF-related protein 1 (CTRP1) in the radio-sensitivity of GBMs, utilizing both X-ray and carbon ion irradiation. Expression analyses revealed elevated CTRP1 and CD133 levels in GBMs tissues, which were associated with poor patient survival. Carbon ion irradiation demonstrated superior growth inhibition compared to X-ray, particularly in U87 (high CD133) cells. Moreover, CTRP1 expression increased following radiation exposure, especially after X-ray treatment. Knockdown of CTRP1 enhanced radio-sensitivity by reducing cell proliferation and increasing apoptosis, while exacerbating oxidative stress. Bioinformatics analysis revealed CTRP1's involvement in DNA damage repair pathways. Our findings establish a novel connection between CTRP1 and cellular radio-sensitivity. Targeting CTRP1, especially in U87 (high CD133) cells, enhances GBMs radio-sensitivity, offering potential therapeutic avenues.

CTRP9 attenuates peripheral nerve injury-induced mechanical allodynia and thermal hyperalgesia through regulating spinal microglial polarization and neuroinflammation mediated by AdipoR1 in male mice

Peripheral nerve injury triggers rapid microglial activation, promoting M1 polarization within the spinal cord, which exacerbates the progression of neuropathic pain. C1q/TNF-related protein 9 (CTRP9), an adiponectin homolog, is known to suppress macrophage activation and exhibit anti-inflammatory properties through the activation of adiponectin receptor 1 (AdipoR1) in various disease contexts. Nevertheless, the involvement of CTRP9 in microglial polarization in the context of neuropathic pain is still unclear. Our study aimed to how CTRP9 influences spinal microglial polarization, neuroinflammation, and pain hypersensitivity, as well as the underlying mechanism, using a neuropathic pain model in male mice with spared nerve injury (SNI) of sciatic nerve. Our findings revealed SNI elevated the spinal CTRP9 and AdipoR1 levels in microglia. Furthermore, intrathecal administration of recombinant CTRP9 (rCTRP9) substantially weakened mechanical hypersensitivity and heat-related pain response triggered by SNI. On the other hand, rCTRP9 mediated a phenotypic switch in microglia, from the pro-inflammatory M1 state to the anti-inflammatory M2 state, by influencing the spinal AMPK/NF-κB mechanism in SNI mice. Additionally, treatment with AdipoR1 siRNA or an AMPK-specific antagonist both reversed the effects of CTRP9 on the phenotypic switching of spinal microglia and pain hypersensitivity. Collectively, these results indicate that CTRP9 ameliorates mechanical hypersensitivity and heat-related pain response, shifted the balance of microglia towards the anti-inflammatory M2 state, and suppresses neuroinflammatory responses by modulating the AMPK/NF-κB pathway, mediated by AdipoR1 activation, in mice with SNI.Graphical

CTRP 9 mitigates the apoptosis and unfolded protein response of OGD/R-induced retinal ganglion cells by regulating the AMPK pathway.

C1q/TNF-related protein-9 (CTRP9) has been reported to play roles in several types ofretinal diseases. However, therole and thepotential mechanism ofCTRP9 in glaucoma are still incompletely understood. Theexpression ofCTRP9 in OGD/R-induced retinal ganglion cells (RGCs) was detected by quantitative real-time polymerase chain reaction and western blot assay. Cell proliferation was identified by cell counting Kit-8 assay. Flow cytometry, enzyme-linked immunosorbent assay and western blot assay were performed to assess cell apoptosis. Unfolded protein response (UPR), endoplasmic reticulum (ER) stress and theAMPK pathway were evaluated by western blot assay. Thedata showed that theexpression ofCTRP9 was significantly downregulated in OGD/R-induced 661W cells. OGD/R treatment reduced cell viability, promoted cell apoptosis and activated theUPR and ER stress. Theoverexpression ofCTRP9 reversed theeffects ofOGD/R on 661W cell viability, apoptosis, theUPR and ER stress, as well as theAMPK pathway. However, Compound C, an inhibitor ofAMPK signaling, reversed theprotection ofCTRP9 overexpression against injury from OGD/R in 661W cells. In summary, theresults revealed that CTRP9 abated theapoptosis and UPR ofOGD/R-induced RGCs by regulating theAMPK pathway, which may provide apromising target for thetreatment ofglaucoma.

CTRP9 alleviates hypoxia/reoxygenation-induced human placental vascular endothelial cells impairment and mitochondrial dysfunction through activating AMPK/Nrf2 signaling

BackgroundPregnancy-induced hypertension (PIH) is associated with significant maternal and fetal mortality. The present study is aimed at exploring the molecular mechanism of C1q/TNF-related protein 9 (CTRP9) in PIH. MethodsHuman placental vascular endothelial cells (HPVECs) underwent hypoxia/reoxygenation (H/R) to construct an in vitro PIH cellular model. Cell transfection was conducted to over-express CTRP9. The expression level of CTRP9 was determined by western blot and quantitative real-time PCR. CCK-8, flow cytometry, wound-healing and tube formation assays were conducted to assess cell viability, apoptosis, migration and angiogenesis, respectively. Mitochondrial membrane potential (∆ψm) was evaluated adopting JC-1 staining. Mitochondrial ROS and copy number (mtDNA) were examined using superoxide indicator and real-time PCR, respectively. Then, HPVECs were pre-treated with Compound C (CC), the inhibitor of AMPK, for regulatory mechanism research. ResultsCTRP9 was downregulated in HPVECs exposed to H/R induction. CTRP9 overexpression retards H/R-mediated cell viability loss and apoptosis, impaired migration and angiogenesis of HPVECs. Meanwhile, CTRP9 overexpression alleviates H/R-mediated mitochondrial dysfunction in HPVECs by enhancing mitochondrial ∆ψm, reducing mitochondrial ROS generation and increasing mtDNA copies. In addition, CTRP9 activated AMPK/Nrf2 signaling in H/R-mediated HPVECs, and additional treatment of CC greatly weakened the functional effects of CTRP9 in H/R-mediated HPVECs. ConclusionOur results suggested that CTRP9 protected against H/R-mediated HPVECs injuries dependent on AMPK/Nrf2 signaling and could be applied as a potential therapy for PIH.

Abstract P432: CTRP1 Contributes To Angiotensin II-Induced Hypertension Via Activation Of Intrarenal Renin

C1q/TNF-related protein 1(CTRP1) is generally regarded as an adipokine and its circulating level is elevated in patients with hypertension. However, the functional role and mechanism of CTRP1 in blood pressure (BP) regulation largely remains elusive. In the present study, we investigated the BP phenotype of global CTRP1 knockout mice (termed CTRP1 KO) during angiotensin II (AngII) infusion and further explored the underlying mechanism involving the intrarenal renin. At baseline, 4-mo-old CTRP1 KO mice exhibited no developmental abnormalities or had normal BPs as compared with wild-type controls (WT). AngII infusion (300 ng/min/kg) induced a 3-fold increase in plasma and urinary CTRP1 levels as assessed by ELISA, but it was undetectable in CTRP1 KO mice. By radiotelemetry, AngII-infused CTRP1 KO mice exhibited reduced MAP as compared with AngII-infused WT mice (MAP [mmHg] in Day 7: 124.1 ± 2.4 in CTRP1 KO mice vs. 135 ± 3.1 in WT mice, n = 4 for each group, p < 0.05 by Student’s t test). This reduction was accompanied by a diminished response in intrarenal renin expression, as evidenced by urinary total prorenin/renin excretion ([ng/24h]: 0.51 ± 0.08 in WT/Vehicle vs. 1.22 ± 0.12 in WT/AngII; 0.32 ± 0.11 in CTRP1 KO/Vehicle vs. 0.54 ± 0.09 in CTRP1 KO/AngII; p < 0.05 by Two-way ANOVA analysis) and renal medullary mRNA levels (qRT-PCR: 1.00 ± 0.18 in WT/Vehicle vs. 3.73 ± 0.59 in WT/AngII; 0.52 ± 0.21 in CTRP1 KO/Vehicle vs. 1.31 ± 0.37 in CTRP1 KO/AngII, p < 0.05 by Two-way ANOVA analysis). In contrast, renal cortical renin mRNA was suppressed by AngII infusion more significantly in WT than in CTRP1 KO mice. In cultured mouse collecting duct-derived M-1 cells, treatment with recombinant human CTRP1-His protein (hCTRP1-His) at 20 nM for 24 hours consistently upregulated renin expression at both protein (Densitometry: 1.00 ± 0.23 in Vehicle group vs. 2.58 ± 0.42 in hCTRP1-His group, p < 0.05) and mRNA levels (qRT-PCR: 1.00 ± 0.12 in Vehicle group vs. 11.60 ± 1.21 in hCTRP1-His group, p < 0.05) levels. Collectively, these findings provide evidence favoring CTRP1 as a regulator of intrarenal renin mediating AngII-induced hypertension and further suggest CTRP1 as a potential mediator of adipose-renal crosstalk.

Ubiquitin-specific protease 11-mediated CD36 deubiquitination acts on C1q/TNF-related protein 9 against atherosclerosis.

Atherosclerosis is a huge threaten to the human health, C1q/TNF-related protein 9 (CTRP9) has been previously reported possessing vascular protective functions. Our study is aimed to reveal the mechanism of the regulative effects of CTRP9 on the foam cell formation. Primary human macrophages were isolated from human monocytes donated by healthy volunteers. CCK-8 assay was performed for determining the cell viability. Oil Red O staining was employed for measuring the lipid accumulation. Cholesterol ester and cholesterol concentration were detected by commercial kits for evaluating the intracellular cholesterol. Ubiquitination assay was performed to reveal the ubiquitination level of CD36, cycloheximide assay was applied for determining the half-life of CD36 protein. Quantitative real-time PCR and western blot assays were performed for detecting the mRNA and protein expression. Pre-treatment with CTRP9 in primary human macrophages markedly suppressed the cholesterol accumulation concentration after oxidized low-density lipoprotein treatment. CD36 was significantly increased after oxidized low-density lipoprotein exposure while was reduced by CTRP9 treatment. Up-regulation of CD36 significantly reversed the CTRP9-mediated protective effects in foam cells. The differential expression levels of several deubiquitinating enzymes preliminarily indicated that USP11 was obviously decreased after CTRP9 treatment. USP11 knockdown decreased the CD36 protein expression and pre-treatment with 10μg/mL MG132 significantly maintained the CD36 level from USP11 knock down. Up-regulation of CD36 reversed the alterations on the cholesterol metabolism caused by CTRP9 or USP11 knockdown. CTRP9 regulates the USP11/CD36 axis to protect the macrophages form transforming into foam cells by suppressing intracellular lipid and cholesterol accumulation, which is a potential therapeutic agent for atherosclerosis.

Association Between Circulating Levels of C1q/TNF-Related Protein-9 and Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis.

According to growing research, C1q/TNF-Related Protein-9 (CTRP9) appears to be linked to type 2 diabetes mellitus (T2DM). But the literature on circulating levels of CTRP9 in patients with T2DM has been contradictory. This is a systematic review and meta-analysis to reassess the circulating level of CTRP9 in patients with T2DM, with and without complications. Relevant studies published until October 31, 2021, were identified from the PubMed, Embase, Web of Science, Cochrane Library, WanFang, CNKI, VIP, and CBM databases. Participants with age ≥18 years with clinically diagnosed T2DM were included. Sex and diabetes complications were not restricted. The data were extracted by 2 reviewers independently using a standard data collection form. Analysis demonstrated significantly lower circulating levels of CTRP9 in patients with T2DM than in patients without diabetes (standardized mean difference [SMD] = -1.36; 95% CI -1.78 to -0.93; P < .001), I2 = 97.5%, P < .001). Furthermore, the circulating level of CTRP9 in patients with T2DM-related complications was lower than that in patients with T2DM without complications, regardless of macrovascular complications or microvascular complications (SMD = -1.062; 95% CI -1.466 to -0.658; P < .001, I2 = 91.3%, P < .001). Subgroup analyses revealed that factors such as body mass index, T2DM duration, and fasting blood glucose were the sources of heterogeneity (P = .047, P = .034, and P = .07, respectively). The present systematic review and meta-analysis found CTRP9 levels were lower in T2DM patients with or without complications. However, since this was a meta-analysis of most observational studies, these findings still need to be verified by further studies with a large sample size.

The Impact of Obesity on C1q/TNF-Related Protein-9 Expression and Endothelial Function following Acute High-Intensity Interval Exercise vs. Continuous Moderate-Intensity Exercise.

C1q-TNF-related protein-9 (CTRP9) increases endothelial nitric oxide synthase and reduces vasoconstrictors. There is limited information regarding exercise-mediated CTRP9 in obesity. The purpose of this study was to compare high-intensity interval exercise (HIIE) and continuous moderate-intensity exercise (CME) on the CTRP9 response and an indicator of endothelial function (FMD) in obese participants. Sixteen young male participants (9 obese and 7 normal-weight) participated in a counterbalanced and caloric equated experiment: HIIE (30 min, 4 intervals of 4 min at 80-90% of VO2 max with 3 min rest between intervals) and CME (38 min at 50-60% VO2 max). Serum CTRP9 and FMD were measured prior to, immediately following exercise, and 1 h and 2 h into recovery. CTRP9 was significantly increased immediately following acute HIIE and CME in both groups (p = 0.003). There was a greater CME-induced FMD response at 2 h into recovery in obese participants (p = 0.009). A positive correlation between CTRP9 and FMD percent change was observed in response to acute CME when combined with both obese and normal-weight participants (r = 0.589, p = 0.016). The novel results from this study provide a foundation for additional examination of the mechanisms of exercise-mediated CTRP9 on endothelial function in individuals with obesity.

Effect of C1q/TNF-Related Protein 9 on Coronary Artery Calcification: An Observational Study.

Coronary artery calcification (CAC) increases the risk of acute coronary syndrome. This study examined the correlation between C1q/TNF-related protein 9 (CTRP9) and CAC and explored CTRP9 as a biomarker for prognosis. We divided 275 patients with coronary heart disease into four groups. In order to balance the baseline confounding factors, propensity score matching (PSM) was performed to match CAC patients with non-CAC patients in a 1:1 ratio. Optical coherence tomography (OCT) calcification scoring was performed in 126 patients with CAC. Moreover, 140 patients who underwent OCT were followed-up for 9 months for analysis of the correlation between CTRP9 levels and clinical prognosis. Based on OCT calcification scores, 126 patients with CAC were divided into the 0–2 and 3–4 groups. Plasma CTRP9 levels were significantly lower in the type 2 diabetes mellitus (T2DM), CAC and CAC with T2DM groups than in the control group. CTRP9 played roles as a protective factor and potential predictor in CAC severity. The AUC of the OCT calcification score 3–4 group predicted by the plasma CTRP9 level was 0.766. During the follow-up period, the cumulative event-free survival rate was significantly lower in the low-level CTRP9 (L-CTRP9) group than in the high-level (H-CTRP9) group, and the incidence of major endpoint events was significantly higher in the L-CTRP9 group than in the H-CTRP9 group. CTRP9 can be a valuable biomarker for CAC occurrence and severity and can predict patients’ clinical prognosis.

Increased Levels of ANGPTL3 and CTRP9 in Patients With Obstructive Sleep Apnea and Their Relation to Insulin Resistance and Lipid Metabolism and Markers of Endothelial Dysfunction.

Obstructive sleep apnea (OSA) has a close relation with obesity and perturbation in adipokines and hepatokines, which are linked to OSA consequences such as insulin resistance, dyslipidemia, and endothelial dysfunction. This study aimed to assess the relation of C1q/TNF-related protein 9 (CTRP9) and angiopoietin-like protein 3 (ANGPTL3) with OSA and biochemical measurements. Serum levels of ANGPTL3, CTRP9, adiponectin, leptin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion protein 1 (VCAM-1) were determined in 74 OSA patients and 27 controls using enzyme-linked immunosorbent assay kits. Levels of ANGPTL3, CTRP9, leptin, ICAM-1, and VCAM-1 were increased in the patients compared to the controls, whereas adiponectin levels decreased. ANGPTL3 had a positive correlation with total cholesterol, triglyceride, low-density lipoprotein cholesterol, ICAM-1, and VCAM-1 and was inversely correlated with leptin. CTRP9 showed a positive correlation with body mass index, insulin resistance, ICAM-1, and VCAM-1. The results indicated the relation of ANGLTP3 and CTRP9 with OSA and its complications, which suggested a possible role for these factors in the consequences of OSA.

1046-P: Role of Serum C1q/TNF-Related Protein 9 in Predicting Gestational Diabetes Mellitus

Background/Aims: C1q/TNF-related protein 9 (CTRP9) as a member of CTRP super family, participates in the regulation of glycolipid metabolism. However information regarding the role of CTRP9 in gestational diabetes mellitus (GDM) is scarce. The current study aims to ascertain the relationship between serum CTRP9 levels and GDM. Methods: A total of 35 GDM patients and 37 normal pregnant women were enrolled in our study. Serum CTRP9 levels were measured via enzyme-linked immunosorbent assay (ELISA) . Fasting insulin (FINS) , IL-6, Leptin, MCP-1, TNF-α and IL-1β were quantified using Luminex-xMAP technology. Anthropometric data and biochemical parameters were also obtained or measured. Results: The results showed that fasting plasma glucose (FPG) , one hour plasma glucose (1-h PG) , 2 hour plasma glucose (2-h PG) , FINS, IL-6, Leptin, TNF-α and CTRP9 during GDM group were significantly higher than the control group. In addition, serum CTRP9 levels had a significantly positive correlation with FPG (r = 0.559, P &amp;lt; 0.001) , 1h-PG (r = 0.539, P &amp;lt;0.0) , 2h-PG (r = 0.378, P = 0.001) , FINS (r = 0.253, P = 0.032) , HOMA-IR (r = 0.382, P = 0.001) , IL-6 (r = 0.283, P = 0.016) , and TNF-α (r = 0.266, P = 0.024) . Furthermore, binary logistic regression demonstrated that HOMA-IR and CTRP9 were independent risk factors for GDM. The AUC-ROC indicated that the diagnostic efficiency of combined CTRP9 and HOMA-IR was much higher than a single index. Conclusions: The high level of serum CTRP9 is an independent risk factor for GDM. Moreover, the combination of serum CTRP9 and HOMA-IR were more efficient in diagnosing GDM. Key words: Gestational diabetes mellitus, CTRP9, insulin resistance Disclosure H. Zhang: None.

CTRP9 overexpression attenuates palmitic acid-induced inflammation, apoptosis and impaired migration in HTR8/SVneo cells through AMPK/SREBP1c signaling.

Obesity in pregnant mothers often leads to a range of obstetric complications, including miscarriage, pre-eclampsia, gestational hypertension and diabetes. C1q/TNF-related protein 9 (CTRP9) is an adipokine with an anti-inflammatory effect. The aim of the present study was to identify the role of CTRP9 in the pathogenesis of maternal obesity during pregnancy. Following treatment with palmitic acid (PA), HTR8/SVneo cell viability and CTRP9 expression were analyzed using Cell Counting Kit-8 (CCK-8), reverse transcription-quantitative PCR (RT-qPCR) and western blot analyses. The effects of CTRP9 overexpression on cell viability, apoptosis, pro-inflammatory cytokine levels and migration were assessed using CCK-8, TUNEL, RT-qPCR and Transwell assays, respectively. Subsequently, sterol-regulatory element binding protein 1c (SREBP1c) overexpression efficiency was verified using RT-qPCR, and its effects on cell viability, apoptosis, pro-inflammatory cytokines and migration damage were then examined in HTR8/SVneo cells. The results showed that CTRP9 overexpression attenuated the inhibition of cell viability and apoptosis caused by PA in HTR8/SVneo cells, reduced pro-inflammatory cytokine release, improved cell migration and regulated the protein expression level of AMP-activated protein kinase (AMPK)/SREBP1c signaling. In addition, CTRP9 inhibited SREBP1c expression through AMPK signaling, thereby attenuating the inflammation, apoptosis and inhibited migration caused by PA in HTR8/SVneo cells. In brief, CTRP9 protected against inflammation, apoptosis and migration defects in HTR8/SVneo cells exposed to PA treatment through AMPK/SREBP1c signaling, which suggested the potential role of CTRP9 in alleviating the toxicity of PA.

Study of relation between Serum C1Q / TNF-Related Protein 9 (CTRP9) and Diabetic Retinopathy in a Sample of Egyptian Patients With Type 2 Diabetes Mellitus

Study of relation between Serum C1Q / TNF-Related Protein 9 (CTRP9) and Diabetic Retinopathy in a Sample of Egyptian Patients With Type 2 Diabetes Mellitus

C1q/TNF-related protein-1: Potential biomarker for early diagnosis of autism spectrum disorder.

IntroductionAutism spectrum disorders (ASDs) are neurodevelopmental diseases characterized by communication inabilities, social interaction impairment, repetitive behavior, as well as learning problems. Although the exact mechanism underlying this disease is still obscure, researchers believe that several factors play a significant role in its development and pathogenesis. Some authors have reported an association between adipokines family and autism. C1q/TNF-related protein-1 (CTRP1) is a member of the adipokines family, and we hypothesized that this adipokine might have an influential role in the pathogenesis of ASDs. Since there is no specific marker for screening the disease, we evaluated CTRP1 as a potential marker for achieving this purpose.MethodsBlood samples were collected from 82 (41 ASDs boys, 41 healthy boys as controls) children aged 5–7 years old. CTRP1 gene expression and CTRP1 serum level were measured by quantitative realtime-PCR and enzyme-linked immunosorbent assay methods, respectively.ResultsIt was found that CTRP1 is significantly elevated in autistic children in comparison to healthy controls, both at the gene expression level, as well as at the serum level; demonstrating a good diagnostic value with a good range of sensitivity and specificity for detecting ASDs.ConclusionCTRP1 expression is elevated in ASDs boys aged 5–7 years old, suggesting a role for this adipokine in ASDs pathophysiology. Also, receiver operating characteristic curve analyses revealed that this adipokine could be utilized as a diagnostic biomarker for differentiating ASDs patients from healthy individuals along with other recently proposed biomarkers.

CTRP9 Mitigates the Progression of Arteriovenous Shunt-Induced Pulmonary Artery Hypertension in Rats.

The present study is aimed at investigating the molecular mechanism of C1q/TNF-related protein 9 (CTRP9) and providing a new perspective in arteriovenous shunt-induced pulmonary arterial hypertension (PAH). PAH was established by an arteriovenous shunt placement performed in rats. Adenovirus(Ad)-CTRP9 and Ad-green fluorescent protein viral particles were injected into the rats through the tail vein. Following 12 weeks, the mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP) were measured and morphological analysis was conducted to confirm the establishment of the PAH model. The systemic elevation of CTRP9 maintained pulmonary vascular homeostasis and protected the rats from dysfunctional and abnormal remodeling. CTRP9 attenuated the pulmonary vascular remodeling in the shunt group by decreasing the mPAP and RVSP, which was associated with suppressed inflammation, apoptosis, and extracellular matrix injury. In addition, CTRP9 dramatically increased the phosphorylation of AKT and p38-MAPK in the lung tissues of shunt-operated animals. These findings suggest a previously unrecognized effect of CTRP9 in pulmonary vascular homeostasis during PAH pathogenesis.

ER-associated CTRP1 regulates mitochondrial fission via interaction with DRP1

C1q/TNF-related protein 1 (CTRP1) is a CTRP family member that has collagenous and globular C1q-like domains. The secreted form of CTRP1 is known to be associated with cardiovascular and metabolic diseases, but its cellular roles have not yet been elucidated. Here, we showed that cytosolic CTRP1 localizes to the endoplasmic reticulum (ER) membrane and that knockout or depletion of CTRP1 leads to mitochondrial fission defects, as demonstrated by mitochondrial elongation. Mitochondrial fission events are known to occur through an interaction between mitochondria and the ER, but we do not know whether the ER and/or its associated proteins participate directly in the entire mitochondrial fission event. Interestingly, we herein showed that ablation of CTRP1 suppresses the recruitment of DRP1 to mitochondria and provided evidence suggesting that the ER–mitochondrion interaction is required for the proper regulation of mitochondrial morphology. We further report that CTRP1 inactivation-induced mitochondrial fission defects induce apoptotic resistance and neuronal degeneration, which are also associated with ablation of DRP1. These results demonstrate for the first time that cytosolic CTRP1 is an ER transmembrane protein that acts as a key regulator of mitochondrial fission, providing new insight into the etiology of metabolic and neurodegenerative disorders.

Relation between Serum C1Q/TNF-Related Protein9 (CTRP9) and Diabetic Retinopathy in a Sample of Egyptian Patients With Type2 DM

Relation between Serum C1Q/TNF-Related Protein9 (CTRP9) and Diabetic Retinopathy in a Sample of Egyptian Patients With Type2 DM

Abstract P160: C1q/TNF-related Protein 1 Induces Obesity-related Hypertension In Mice Via Renal Na+ Retention In The Proximal Tubules

A recently identified adipokine C1q/TNF-related protein 1 (CTRP1) displayed a potent beneficial effect in managing metabolic disorders during type 2 diabetes and obesity. However, little is known about a potential role of CTRP1 in regulation of renal function and blood pressure (BP) in the context of obesity. Therefore, the present study aimed to determine the effect of a recombinant CTRP1 protein (termed CTRP1-His) on blood pressure in mice with diet-induced obesity (DIO). 8-mo-old male C57/B6 mice were fed a high-fat diet (60 Kcal% fat) for eight weeks and were infused with vehicle or CTRP1-His (10 ng/min/kg) via subcutaneously implanted osmotic minipump for the last seven days. BP parameters were recorded using telemetry devices. Consistent with other groups’ studies, mice infused with CTRP1-His exhibited remarkably improved multiple metabolic parameters, including hyperglycemia and hyperinsulinemia. Compared to the vehicle group, BP responses to CTRP1-His treatment developed a modest but significant increase in BP (MAP on day 7 [mmHg]: 122.3 ± 2.2 vs. 109 ± 1.73, n = 3 per each group, p &lt; 0.01) accompanied with decreased hematocrit (Hct [%]: 43.8 ± 1.3 vs. 49 ± 1.2 %, p &lt; 0.05), an index of plasma volume expansion. The DIO mice infused with CTRP1-His demonstrated a reduced urinary sodium excretion (U Na /Creatinine [mmol/mg]: 0.17 ± 0.04 vs. 0.27 ± 0.06, p = 0.07). By immunoblotting CTRP1-His infusion induced significant upregulation of renal abundances of p-NHE3, V2R, and AQP2 but suppressed obesity-induced renal abundances of p-NCC/NCC, p-NKCC2/NKCC2, and cleaved α-ENaC protein. Interestingly, CTRP1-His infusion tends to decrease albuminuria (urine albumin/Creatinine [mg/g]: 78.8 ± 7.7 vs. 120.5 ± 14, p = 0.07) in the DIO mice. Overall, our results indicated that CTRP1-His exerted a pressor effect in DIO mice via stimulating sodium-water retention through activation of NHE3 and AQP2 associated with compensatory attenuation of Na+ transporters in the distal nephron.

C1q/TNF-related protein 9 decreases cardiomyocyte hypoxia/reoxygenation-induced inflammation by inhibiting the TLR4/MyD88/NF-κB signaling pathway.

C1q/TNF-related protein 9 (CTRP9) acts as an adipokine and has been reported to exert numerous biological functions, such as anti-inflammatory and anti-oxidative stress effects, in ischemic heart disease. In the present study, the role of CTRP9 in neonatal rat cardiomyocytes (NRCMs) following hypoxia/reoxygenation (H/R) and the underlying mechanism was investigated. Adenoviral vectors containing CTRP9 or green fluorescent protein were transfected into NRCMs. A H/R model was constructed 2 days after transfection by 2 h incubation under hypoxia followed by 4 h of reoxygenation. Lactate dehydrogenase (LDH), creatine kinase (CK) and CK-myocardial band (CK-MB) levels were detected by a biochemical analyzer using biochemical kits. In addition, cell viability was detected using trypan blue staining to determine the extent of cell injury. Inflammatory cytokines TNF-α, IL-6 and IL-10 were measured by ELISA. Western blotting and reverse transcription-quantitative PCR were used to evaluate the expression levels of CTRP9, toll-like receptor 4 (TLR4), myeloid differentiation primary response (MyD88) and NF-κB. The DNA binding activity of NF-κB was also detected using an electrophoretic mobility shift assay. The results indicated that transfection with adenoviral vectors containing CTRP9 could markedly enhance CTRP9 expression. CTRP9 overexpression increased cell viability and decreased the release of LDH, CK and CK-MB. In addition, CTRP9 overexpression reduced TNF-α and IL-6 levels whilst increasing IL-10 levels, but decreased the expression of TLR4, MyD88 and NF-κB. Furthermore, the DNA binding activity of NF-κB under H/R was also decreased by CTRP9 overexpression. In conclusion, the results of the present study suggested that CTRP9 could protect cardiomyocytes from H/R injury, which was at least partially due to the inhibition of the TLR4/MyD88/NF-κB signaling pathway to reduce the release of inflammatory cytokines.