C1q/TNF-related protein-9 is elevated in hypertension and associated with the occurrence of hypertension-related atherogenesis.

C1q-tumor necrosis factor-related protein-9 (CTRP9) is an important adipocytokine that is closely associated with cardiovascular disease. This study aimed to detect CTRP9 expression in hypertensive patients and mice and to analyze its effects on hypertension-related atherogenesis. First, circulating CTRP9 levels were detected in both nonhypertensive subjects and hypertensive patients. The results showed that plasma CTRP9 levels were increased in hypertension patients compared with control subjects and gradually elevated in the Grade I, Grade II, and Grade III groups. While nondipper state did not affect CTRP9 expression in hypertension patients. Hypertension patients with carotid atherosclerotic plaque (CAP) exhibited higher CTRP9 levels and the high CTRP9 group exhibited significantly higher CAP morbidity, CTRP9 levels were positively correlated with the occurrence of CAP. Then, effects of CTRP9 on angiotensin II (Ang II)-induced endothelial dysfunction were analyzed in vitro, and the results exhibited that treatment with Ang II significantly increased CTRP9 mRNA expression in endothelial cells (ECs), and downregulation of CTRP9 expression aggravated Ang II-induced endothelial dysfunction in ECs. Mice were infused with Ang II, and CTRP9 was also increased in Ang II-infused mice and mainly secreted by ECs. In Ang II-infused ApoE-/- mice, treatment with recombinant CTRP9 significantly reduced atherosclerotic area and alleviated endothelial dysfunction. In conclusion, our results may found that CTRP9 delayed the progression of hypertension-related arteriosclerosis by alleviating endothelial dysfunction.

[The clinical significance of serum C1q tumor necrosis factor-related protein-9 (CTRP9) in patients with cerebral infarction].

To explore the clinical significance of C1q tumor necrosis factor-related protein-9 (CTRP9) in patients with cerebral infarction. Our data showed that the serum CTRP9 was significantly lower than that of control group, especially in patients with large artery atherosclerotic cerebral infarction. CTRP9 was first decreased and even lower from day 4 to day 10, then gradually elevated. Logistic regression analysis suggested that high CTRP9 level was a protective factor for cerebral infarction. Thus, CTRP9 could be a factor for further classification of cerebral infarction and provides a potential option for disease prevention and treatment.

Targeted deletion of C1q/TNF-related protein 9 increases food intake, decreases insulin sensitivity, and promotes hepatic steatosis in mice.

Transgenic overexpression of CTRP9, a secreted hormone downregulated in obesity, confers striking protection against diet-induced obesity and type 2 diabetes. However, the physiological relevance of this adiponectin-related plasma protein remains undefined. Here, we used gene targeting to establish the metabolic function of CTRP9 in a physiological context. Mice lacking CTRP9 were obese and gained significantly more body weight when fed standard laboratory chow. Increased food intake, due in part to upregulated expression of hypothalamic orexigenic neuropeptides, contributed to greater adiposity in CTRP9 knockout mice. Although the frequency of food intake remained unchanged, CTRP9 knockout mice increased caloric intake by increasing meal size and decreasing satiety ratios. The absence of CTRP9 also resulted in peripheral tissue insulin resistance, leading to increased fasting insulin levels, impaired hepatic insulin signaling, and reduced insulin tolerance. Increased expression of lipogenic genes, combined with enhanced caloric intake, contributed to hepatic steatosis in CTRP9 knockout mice. Loss of CTRP9 also resulted in reduced skeletal muscle AMPK activation and mitochondrial content. Together, these results provide the genetic evidence for a physiological role of CTRP9 in controlling energy balance via central and peripheral mechanisms.

Diagnostic value and prognostic significance of CTRP9 combined with pentraxin-3 in acute coronary syndrome.

The present study aimed to explore the diagnostic value and prognostic significance of C1q/tumor necrosis factor-related protein 9 (CTRP9) combined with pentraxin-3 (PTX-3) in acute coronary syndrome (ACS). A total of 137 patients with coronary heart disease and chest pain were included. Among them, seventy-nine patients with ACS were allocated into a study group and fifty-eight patients with non-cardiac chest pain (NCCP) were allocated into a control group. The serum CTRP9, PTX-3 levels were quantified by ELISA, and their correlation with other ACS-related indexes, diagnostic value for ACS and predictive significance for poor prognosis were analyzed. In addition, the risk factors of the poor prognosis of ACS patients were studied. CTRP9 was lowly expressed and PTX-3 was highly expressed in the serum of ACS patients. CTRP9 was negatively correlated with cardiac troponin I (cTnI), creatine kinase-MB (CK-MB) and high-sensitivity C-reactive protein (hs-CRP) (P<0.05), while PTX-3 was positively correlated with them (P<0.05). Combined detection of CTRP9 and PTX-3 was of high value in the diagnosis and prognosis of ACS patients. In addition, CTRP9 and PTX-3 were independent risk factors for the poor prognosis of ACS. Patients with ACS had lower CTRP9 expression and higher PTX-3 expression than those without ACS. Moreover, the combined detection of CTRP9 and PTX-3 can better evaluate the diagnosis and prognosis of ACS patients.

[Association between serum CTRP9 levels and diabetic retinopathy in patients with type 2 diabetes mellitus].

OBJECTIVE: To investigate the relationship between serum C1q tumor necrosis factor-related protein 9 (CTRP9) level and the risk of diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). OBJECTIVE: A total of 291 patients with T2DM underwent fundus examination, and their serum levels of CTRP9, insulin and adiponectin were measured using enzyme- linked immunosorbent assay. According to results of fundus examination, the patients were divided into DR group and non-DR (NDR) group, and logistic regression was used to analyze the relationship between serum CTRP9 levels and DR in T2DM patients. OBJECTIVE: Compared with those in NDR group, the patients with DR showed significantly increased serum CTRP9 level (P < 0.001) and decreased serum adiponectin level (P < 0.001). Pearson correlation analysis showed that in patients with T2DM complicated by DR, serum CTRP9 levels had a significant positive correlation with DR stage (P < 0.05) and a negative correlation with serum adiponectin level (P < 0.001). Multivariate logistic regression analysis showed that with the increase of serum CTRP9 level, the risk of DR is significantly increased in patients with T2DM. OBJECTIVE: In patients with T2DM complicated by DR, an increased serum CTRP9 level suggests a compensatory response to DR.

C1q/TNF-related protein-9 alleviates airway inflammation in asthma.

BACKGROUNDS: Asthma is characterized as inflammatory disorder in the respiratory system with increasing tendency. Most of the asthma patients suffered from the disease since childhood. Thus, developing novel therapeutic targets of childhood asthma is necessary. Here, we conducted the present study to investigate the effects of CTRP9 (C1q tumor necrosis factor-related protein 9), a newly identified anti-inflammatory factor, on asthma. METHODS: Sixty asthmatic children (30 moderate and 30 mild) were recruited. The mRNA level of CTRP9 in peripheral blood mononuclear cells (PBMCs) and protein level of CTRP9 in serum and induced sputum (IS) samples from asthma patients and healthy controls (HCs) were measured by qPCR and ELISA, respectively. The anti-inflammatory effects of CTRP9 was determined in vitro and potential therapeutic effect on asthma was evaluated in mouse model. RESULTS: The mRNA and protein levels of CTRP9 was significantly down-regulated in asthmatics than HCs. Furthermore, the expression level of CTRP9 was negatively correlated with the expression of TNF-α, IL-1ß, and IL-6 in PBMCs. The CTRP9 significantly suppressed the expression of pro-inflammatory factors in PBMCs and sputum cells from asthma patients in vitro. And delivering CTRP9 into mouse model of asthma showed disease alleviation. CONCLUSION: Our data here indicated that CTRP9 may alleviate airway inflammation and remodeling in asthma.

Down-Regulation of miR-34a-5p Potentiates Protective Effect of Adipose-Derived Mesenchymal Stem Cells Against Ischemic Myocardial Infarction by Stimulating the Expression of C1q/Tumor Necrosis Factor-Related Protein-9.

Adipose-derived stem cells (ADSCs) have shown great promise for the treatment of myocardial infarction (MI), although their potential therapeutic mechanism remains poorly understood. Growing evidence has implicated microRNAs (miRNAs or miRs) in the biological processes whereby ADSCs could ameliorate cardiovascular disease. In this study, we explored the contribution of miR-34a-5p down-regulation to the protective actions of ADSCs against MI. We initially identified the interaction between miR-34a-5p and C1q/tumor necrosis factor-related protein-9 (CTRP9) through in silico analysis. We next tested the effects of miR-34a-5p and CTRP9 on the expression of extracellular signal-regulated kinase 1 (ERK1), matrix metalloproteinase-9 (MMP-9), nuclear factor (erythroid-derived 2)-like 2 (NRF2), and antioxidant proteins [manganese superoxide dismutase (MnSOD), and heme oxygenase-1 (HO-1)] through gain- and loss-of-function tests. In other experiments, we assessed the proliferation, migration, and apoptosis of ADSCs using the EdU assay, scratch test, Transwell assay, and flow cytometry. Finally, we studied whether miR-34a-5p/CTRP9 axis could modulate the protective effect of ADSCs against MI during stem cell transplantation in MI mouse models. miR-34a-5p could target and down-regulate CTRP9 in cardiomyocytes. Down-regulated miR-34a-5p increased the expression of ERK1, MMP-9, NRF2, MnSOD, and HO-1, whereas down-regulation of miR-34a-5p or up-regulation of CTRP9 in vitro promoted ADSC proliferation and migration and inhibited ADSC apoptosis. Moreover, miR-34a-5p down-regulation or CTRP9 up-regulation promoted the protective role of ADSCs against MI damage in vivo. Thus, inhibition of miR-34a-5p may facilitate ADSC's protective function against MI damage by stimulating the expression of CTRP9.

Autoantibodies Against ß1-Adrenoceptor Exaggerated Ventricular Remodeling by Inhibiting CTRP9 Expression.

Background Autoantibodies against the second extracellular loop of the ß1-adrenoceptor (ß1- AA ) act similarly to agonist of ß1-adrenergic receptor, which plays an important role in the pathophysiological characteristics of ventricular remodeling. Recently, considerable lines of evidence have suggested that CTRP9 (C1q tumor necrosis factor-related protein 9) is a potent cardioprotective cardiokine and protects the heart from ventricular remodeling. The aim of this study was to determine the role of CTRP 9 in ventricular remodeling induced by ß1- AA . Methods and Results Blood samples were collected from 131 patients with coronary heart disease and 131 healthy subjects. The serum levels of ß1- AA and CTRP 9 were detected using ELISA . The results revealed that CTRP 9 levels in ß1- AA -positive patients were lower than those in ß1- AA -negative patients, and serum CTRP 9 concentrations were inversely correlated with ß1- AA . ß1- AA monoclonal antibodies (ß1- AA mAbs) were administered in mice with and without rAAV 9- cTnT -Full Ctrp9- FLAG virus for 8 weeks. Reverse transcription-polymerase chain reaction/Western analysis showed that cardiomyocyte CTRP 9 expression was significantly reduced in ß1- AA mAb-treated mice. Moreover, compared with the ß1- AA mAb alone group, cardiac-specific CTRP 9 overexpression improved cardiac function, attenuated adverse remodeling, and ameliorated cardiomyocyte apoptosis and fibrosis. Mechanistic studies demonstrated that CTRP 9 overexpression decreased the levels of G-protein-coupled receptor kinase 2 and promoted the activation of AMP-dependent kinase pathway. However, cardiac-specific overexpression of CTRP 9 had no effect on the levels of  cAMP and protein kinase A activity elevated by ß1-AAmAb. Conclusions This study provides the first evidence that the long-term existence of ß1- AA mAb suppresses cardiac CTRP 9 expression and exaggerates cardiac remodeling, suggesting that CTRP 9 may be a novel therapeutic target against pathologic remodeling in ß1- AA -positive patients with coronary heart disease.

miR-31 Links Lipid Metabolism and Cell Apoptosis in Bacteria-Challenged Apostichopus japonicus via Targeting CTRP9.

The biological functions of microRNAs (miRNAs) have been studied in a number of eukaryotic species. Recent studies on vertebrate animals have demonstrated critical roles of miRNA in immune and metabolic activities. However, studies on the functions of miRNA in invertebrates are very limited. Here, we demonstrated that miR-31 from Apostichopus japonicus disrupts the balance of lipid metabolism, thus resulting in cell apoptosis by targeting complement C1q tumor necrosis factor-related protein 9 (AjCTRP9), a novel adipokine with pleiotropic functions in immunity and metabolism. Lipidomic analysis suggested that the intercellular lipid metabolites were markedly altered, and three ceramide (Cer) species synchronously increased in the AjCTRP9-silenced coelomocytes. Moreover, exogenous Cer exposure significantly induced apoptosis in the coelomocytes in vivo, in agreement with findings from miR-31 mimic- or AjCTRP9 small-interfering RNA-transfected coelomocytes. Furthermore, we found that the imbalance in sphingolipid metabolism triggered by the overproduction of Cers ultimately resulted in the activation of the apoptosis initiator caspase-8 and executioner caspase-3. Our findings provide the first direct evidence that miR-31 negatively modulates the expression of AjCTRP9 and disturbance of Cer channels, thus leading to caspase-3- and caspase-8-dependent apoptosis, during the interactions between pathogens and host.

A brief glimpse at CTRP3 and CTRP9 in lipid metabolism and cardiovascular protection.

Adipose tissue is now known to express and secrete numerous adipokines that not only regulate lipid metabolism but also function in a wide array of physiological or pathological processes. C1q tumor necrosis factor-related protein 3 (CTRP3, also known as CORS26/cartducin) and CTRP9, novel members of the adipokine family, have intersecting functions in the regulation of lipid metabolism and contribute to cardiovascular protection. Here, we focus on the novel advances concerning the roles of CTRP3 and CTRP9 in these processes and review the general mechanisms. This review should serve as a basis for the design of future experimental studies and may implicate these adipokines as future therapeutic targets.