ABSTRACT
Background: In general, the identification of cholesterol-depleted lipid particles can be inferred from non-high-density lipoprotein cholesterol (non-HDL-C) concentration to apolipoprotein B (apoB) concentration ratio, which serves as a reliable indicator for assessing the risk of cardiovascular disease. However, the ability of non-HDL-C/apoB ratio to predict the risk of long-term mortality among the general population remains uncertain. The aim of this study is to explore the association of non-HDL-C/apoB ratio with long-term all-cause and cardiovascular mortality in adults of the United States. Methods: This retrospective cohort study was a further analysis of existing information from the National Health and Nutrition Examination Survey (NHANES). In the ultimate analysis, 12,697 participants from 2005 to 2014 were included. Kaplan-Meier (K-M) curves and the log-rank test were applied to visualize survival differences between groups. Multivariate Cox regression and restricted cubic spline (RCS) models were applied to evaluate the association of non-HDL-C/apoB ratio with all-cause and cardiovascular mortality. Subgroup analysis was conducted for the variables of age, sex, presence of coronary artery disease, diabetes and hypertriglyceridemia and usage of lipid-lowering drugs. Results: The average age of the cohort was 46.8 ± 18.6 years, with 6215 (48.9%) participants being male. During a median follow-up lasting 68.0 months, 891 (7.0%) deaths were documented and 156 (1.2%) patients died of cardiovascular disease. Individuals who experienced all-cause and cardiovascular deaths had a lower non-HDL-C/apoB ratio compared with those without events (1.45 ± 0.16 vs. 1.50 ± 0.17 and 1.43 ± 0.17 vs. 1.50 ± 0.17, both P values < 0.001). The results of adjusted Cox regression models revealed that non-HDL-C/apoB ratio exhibited independent significance as a risk factor for both long-term all-cause mortality [hazard ratio (HR) = 0.51, 95% confidence interval (CI): 0.33-0.80] and cardiovascular mortality (HR = 0.33, 95% CI: 0.12-0.90). Additionally, a significant sex interaction was discovered (P for interaction <0.05), indicating a robust association between non-HDL-C/apoB ratio and long-term mortality among females. The RCS curve showed that non-HDL-C/apoB ratio had a negative linear association with long-term all-cause and cardiovascular mortality (P for non-linearity was 0.098 and 0.314). Conclusions: The non-HDL-C/apoB ratio may serve as a potential biomarker for predicting long-term mortality among the general population, independent of traditional risk factors.
ABSTRACT
BACKGROUND: Fibroblast growth factor 21 (FGF21) regulates glycolipid metabolism and insulin homeostasis and acts as a cardioprotective factor by protecting against myocardial ischemia/reperfusion injury, hypertension, and vascular dysfunction. FGF21 has been reported to prevent Doxorubicin (Dox)-induced cardiotoxicity, and the related signaling pathway is worthy of further study. Connexin43 (Cx43) protein was reduced by Dox treatment, especially low phosphorylated form of Cx43. Thus the aim of study is to explore the protection effect of FGF21 on Dox induced cardiotoxicity by improving the expression of Cx43 and the involved signaling pathway. METHODS AND RESULTS: FGF21 inhibited apoptosis in Dox-treated mice and cardiomyocytes. FGF21 increased the levels of connexin43 phosphorylated at serine (S) 282 (p-Cx43 S282) and total Cx43 to inhibit Dox-induced apoptosis. By RNA sequencing, we found that deubiquitinase monocyte chemoattractant protein-induced protein 1 (MCPIP1) expression was increased by FGF21. We further found that FGF21 induced the phosphorylation of fibroblast growth factor receptor 1 (FGFR1), extracellular signal-regulated kinase 1 and 2 (Erk1/2), and Elk. Phosphorylated Elk translocated to the nucleus and increased the expression of MCPIP1. Then, MCPIP1 bound neural precursor cell expressed developmentally downregulated protein 4 (Nedd4), an E3 ubiquitination ligase, as shown by co-immunoprecipitation (Co-IP), and suppressed Cx43 ubiquitination and degradation, competitively inhibiting the binding of Cx43 with Nedd4. Thus Nedd4 could not bind and ubiquitinate Cx43, leading to the up-regulation of Cx43 and phosphorylation of Cx43 at S282. CONCLUSIONS: FGF21 inhibited the effects of Dox on cardiomyocytes by elevating the phosphorylation of Cx43 at S282 and total Cx43 expression. This study suggests a previously unknown mechanism for the FGF21-mediated enhancement of cardiomyocyte survival and provides an effective approach to protect against the adverse cardiac effects of Dox.
