COMP (Cartilage Oligomeric Matrix Protein), a Novel PIEZO1 Regulator That Controls Blood Pressure

Background: Vascular endothelial cells are critical for maintaining blood pressure (BP) by releasing biologically active molecules, such as nitric oxide. A non-endothelial cell resident matricellular protein, COMP (cartilage oligomeric matrix protein), plays a pivotal role in maintaining cardiovascular homeostasis, but little is known about its regulatory effect on BP. Methods: Mice were infused with AngII (angiotensin II; 450 ng/kg per minute) for 3 days via an osmotic minipump, and BP was monitored by a tail-cuff system. Second-order mesenteric arteries were isolated from mice for microvascular tension measurement. Nitric oxide was detected by an electron paramagnetic resonance technique. Small-interfering RNA transfection, co-immunoprecipitation, bioluminescence resonance energy transfer assays, and patch-clamp electrophysiology experiments were used for further detailed mechanism investigation. Results: COMP −/− mice displayed elevated BP and impaired acetylcholine-induced endothelium-dependent relaxation compared with wild-type mice with or without AngII. Inhibition of eNOS (endothelial nitric oxide synthase) abolished the difference in endothelium-dependent relaxation between wild-type and COMP −/− mice. Furthermore, COMP directly interacted with the C-terminus of Piezo1 via its C-terminus and activated the endogenous Piezo1 currents, which induced intracellular Ca 2+ influx, Ca 2+ /calmodulin-dependent protein kinase type II and eNOS activation, and nitric oxide production. The Piezo1 activator, Yoda1, reduced the difference in endothelium-dependent relaxation and BP in wild-type and COMP − /− mice. Moreover, COMP overexpression increased eNOS activation and improved endothelium-dependent relaxation and BP. Conclusions: Our study demonstrated that COMP is a novel Piezo1 regulator that plays a protective role in BP regulation by increasing cellular Ca 2+ influx, eNOS activity, and nitric oxide production.

PSV-B-28 Late-Breaking: Development and validation of a Total Inflammation Index™ for identifying inflammation in Labrador Retrievers using a pressure walkway

The objective of this trial was to develop an index system to identify inflammation in Labrador Retrievers using a pressure walkway system. Gait analysis data can be difficult to interpret between treatment groups or for identifying low grade inflammation. To calculate the Total Inflammation Index™, the distance away from the ideal score was calculated for four parameters for each dog, including gait lameness score, total pressure index, step/stride ratio, and hind reach. These values were equally weighted and added together to produce the Total Inflammation Index™. For validation, the Total Inflammation Index™ values were compared to biomarker data for inflammation including cartilage oligomeric matrix protein, interleukin-6, creatine kinase, and c-reactive protein. Forty Labrador Retrievers (20 male/20 female) were used in this trial. All dogs were passed over the pressure walkway (Gait4Dogs; CIR Systems, Inc) to obtain gait analysis at baseline, 24h prior to the first 5km run, 24h after the first 5km run, 24h prior to the final 16km run, and 24h after the final 16km run. All biomarkers and the Total Inflammation Index™ were both significantly lower at the pre-exercise timepoints and elevated after post-exercise timepoints (P < 0.01). The Total Inflammation Index™ had significant correlation between timepoints and all biomarkers, including cartilage oligomeric matrix protein (P < 0.01), interleukin-6 (P < 0.05), creatine kinase (P < 0.01), and c-reactive protein (P < 0.05). The Total Inflammation Index™ appears to be a valid assay to evaluate generalized inflammation in Labrador Retrievers, and is in agreement with inflammatory biomarker values.

Cartilage oligomeric matrix protein as a marker of progressive liver fibrosis in biliary atresia

This study aimed to determine whether mRNA and protein levels of cartilage oligomeric matrix protein (COMP), a glycoprotein responsible for modulating homeostasis of extracellular matrix, in the systemic and local liver environments were associated with clinical parameters of biliary atresia (BA) patients and might serve as a biomarker for BA severity. COMP protein levels in the circulation of 96 BA patients and 56 healthy controls and its mRNA and protein expressions in the liver of 20 BA patients and 5 non-BA patients were evaluated using enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and immunohistochemistry, respectively. In the circulation of BA patients, COMP levels were significantly higher than those in healthy controls. Compared with early-stage BA patients, those with advanced-stage including jaundice, fibrosis, and hepatic dysfunction had significantly increased circulating COMP levels. Raised circulating COMP levels were found to be independently correlated with degree of liver fibrosis. Survival analysis showed that elevated circulating COMP levels were significantly associated with decreased survival of BA patients. Receiver-operating characteristic curve analysis unveiled a diagnostic value of circulating COMP as a non-invasive biomarker of BA (AUC = 0.99), with a sensitivity of 100.0% and a specificity of 98.2%. In the liver, both COMP mRNA and protein expressions of BA patients with fibrosis were significantly greater than those of BA patients without fibrosis and non-BA patients. Collectively, increased circulating COMP might reflect unfavorable outcome of BA patients and have potential as a novel biomarker for the disease severity following Kasai-operation.

Serum Cartilage Oligomeric Matrix Protein and Golgi Protein-73: New Diagnostic and Predictive Tools for Liver Fibrosis and Hepatocellular Cancer?

The cartilage oligomeric matrix protein (COMP) and Golgi-protein-73 (GP73) have been proposed as markers of liver fibrosis and hepatocellular carcinoma (HCC). Our aim was to assess the performance of the combination of these markers in diagnosing cirrhosis and predicting HCC development. Sera from 288 consecutive patients with chronic liver diseases were investigated by using COMP and GP73-ELISAs. Dual positivity for COMP (>15 U/L) and GP73 (>20 units) was observed in 24 (8.3%) patients, while 30 (10.4%) were GP73(+)/COMP(−), 37/288 (12.8%) GP73(−)/COMP(+), and 197 (68.5%) GP73(−)/COMP(−). Positivity for both markers was associated with cirrhosis [23/24 (95.8%) for GP73(+)/COMP(+) vs. 22/30 (73.3%) for GP73(+)/COMP(−) vs. 25/37 (67.6%) for GP73(−)/COMP(+) vs. 46/197 (23.4%) for GP73(−)/COMP(−); P < 0.001]. The combination of GP73, COMP, the aspartate aminotransferase/platelets ratio index, and the Fibrosis-4 score had even higher diagnostic accuracy to detect the presence of cirrhosis [AUC (95% CI): 0.916 (0.878–0.946)] or significant liver fibrosis (METAVIR ≥ F2) [AUC (95% CI): 0.832 (0.768–0.883)] than each marker alone. Kaplan-Meier analysis showed that positivity for both GP73 and COMP was associated with higher rates of HCC development (P < 0.001) and liver-related deaths (P < 0.001) during follow-up. In conclusion, the combination of GP73 and COMP seems efficient to detect cirrhosis and predict worse outcomes and the development of HCC in patients with chronic liver diseases.

EXPRESS: Serum Cartilage Oligomeric Matrix Protein is decreased in patients with Pulmonary Hypertension: a potential protective factor

Cartilage oligomeric matrix protein (COMP) was a protective factor in the cardiovascular system. Previous studies showed that hypoxia led to decreased COMP in rat models of pulmonary hypertension (PH). However, the expression pattern of COMP in the PH population was unclear. A total of 35 patients newly diagnosed with PH and 70 controls were enrolled in the study. Circulating COMP concentrations of serum samples were measured by enzyme-linked immunosorbent assay and were analyzed the association with multiple clinical variables. Serum COMP concentrations in the PH group were significantly declined in comparison with age- and sex-matched normal controls, especially in the female subgroup. No significant difference of COMP concentrations was observed in the etiological classification, heart function classification and risk stratification. Major hemodynamic parameters, six-minute walk distance, N-terminal pro brain natriuretic peptide and short-term prognosis were not statistically associated with COMP. However, some echocardiography parameters, like tricuspid annular plane systolic excursion and mean right atrial pressure, were found the negative relation to COMP concentrations. In conclusion, serum COMP levels were decreased in the patients with PH, which was in accordance with its known biological effects. Its association with long-term prognosis was worth further exploring.