No abstract

Objective:Endothelial dysfunction was widely regarded as the initial lesion in the multifactorial pathogenesis of cardiovascular disease (CVD). Serum endocan, a novel endothelial dysfunction biochemical marker, is involved in the development of CVD. Here, we fulfilled a meta-analysis to evaluate the association between CVD and serum endocan levels.Method:The relevant published literature was searched through large literature databases, including PubMed, Embase, Cochrane Library, SinoMed, and Web of Science, up to June 1, 2018. The data were extracted from the studies. Stata software was used to perform a meta-analysis.Result:Fifteen original studies with a total of 1839 patients and 1258 controls fulfilled the inclusion criteria and were included in the study dataset. Meta-analysis showed that the levels of serum endocan in patients with hypertension, coronary artery disease, and coronary slow flow were higher than those in the control group. The pooled standardized mean differences and 95% confidence intervals of endocan concentrations in those 3 groups were 0.53 [0.19–0.86], P < .01; 0.99 [0.51–1.39], P < .01; and 0.62 [0.45–0.78], P < .01, respectively. Further analysis showed that the level of serum endocan in hypertension patients with coronary artery disease was higher than that in patients with hypertension (0.61 [0.30–0.92], P < .01). Sensitivity analysis and subgroup analysis were use to confirm the above results.Conclusions:In this meta-analysis, we further confirmed that serum endocan level was significantly increased in the CVD population. The high serum endocan level may be one of the risk factors for CVD.

Myofibroblast transformation is a key process in the pathogenesis of lung fibrosis. We have previously reported that hyperoxia induces RhoA activation in HFL-1 lung fibroblasts and RhoA mediates collagen synthesis in hyperoxic lung fibrosis. In the present study, we investigated the role of RhoA and actin cytoskeleton in hyperoxia-induced myofibroblast transformation. Exposure of HFL-1 lung fibroblasts to hyperoxia stimulated actin filament formation, shift of G-actin to F-actin, nuclear co-localization of myocardin-related transcription factor-A (MRTF-A), recruitment of MRTF-A to α-smooth muscle actin (α-SMA) gene promoter, myofibroblast transformation, and collagen-I synthesis. Inhibition of RhoA by C3 transferase CT-04 or dominant-negative RhoA mutant T19N, and inhibition of ROCK by Y27632 prevented myofibroblast transformation and collagen-I synthesis. Moreover, inhibition of RhoA by CT-04 prevented hyperoxia-induced actin filament formation, shift of G-actin to F-actin, and nuclear co-localization of MRTF-A. In addition, disrupting actin filaments by cytochalasin D or scavenging reactive oxygen species (ROS) by tiron attenuated actin filament formation, nuclear co-localization of MRTF-A, myofibroblast transformation, and collagen-I synthesis. Furthermore, overexpression of constitutively active RhoA mutant Q63L or stabilization of actin filaments recapitulated the effect of hyperoxia on actin cytoskeleton, and nuclear co-localization of MRTF-A, myofibroblast transformation and collagen-I synthesis. Interestingly, knocking-down MRTF-A prevented hyperoxia-induced increase in the recruitment of MRTF-A to serum response factor (SRF) transcriptional complex on α-SMA gene promoter, myofibroblast transformation and collagen-I synthesis. Finally, Y27632 and tiron attenuates hyperoxia-induced increases in α-SMA and collagen-I in mouse lungs. Together, these results indicate that the actin cytoskeletal reorganization due to ROS/RhoA-ROCK pathway mediates myofibroblast transformation and collagen synthesis in lung fibrosis of oxygen toxicity. MRTF-A contributes to the regulatory effect of actin cytoskeleton on myofibroblast transformation during hyperoxia.