Metal mixtures with longitudinal changes in lipid profiles: findings from the manganese-exposed workers healthy cohort.

The majority of epidemiological investigations on metal exposures and lipid metabolism employed cross-sectional designs and focused on individual metal. We explored the associations between metal mixture exposures and longitudinal changes in lipid profiles and potential sexual heterogeneity. We recruited 250 men and 73 women, aged 40 years at baseline (2012), and followed them up in 2020, from the manganese-exposed workers healthy cohort. We detected metal concentrations of blood cells at baseline with inductively coupled plasma mass spectrometry. Lipid profiles were repeatedly measured over 8 years of follow-up. We performed sparse partial least squares (sPLS) model to evaluate multi-pollutant associations. Bayesian kernel machine regression was utilized for metal mixtures as well as evaluating their joint impacts on lipid changes. In sPLS models, a positive association was found between manganese and change in total cholesterol (TC) (beta = 0.169), while a negative association was observed between cobalt (beta = - 0.134) and change in low density lipoprotein cholesterol (LDL-C) (beta = - 0.178) among overall participants, which were consistent in men. Interestingly, rubidium was positively associated with change in LDL-C (beta = 0.273) in women, while copper was negatively associated with change in TC (beta = - 0.359) and LDL-C (beta = - 0.267). Magnesium was negatively associated with change in TC (beta = - 0.327). We did not observe the significantly cumulative effect of metal mixtures on lipid changes. In comparison to other metals, manganese had a more significant influence on lipid change [group PIP (0.579) and conditional PIP (0.556) for TC change in men]. Furthermore, male rats exposed to manganese (20 mg/kg) had higher levels of LDL-C in plasma and more apparent inflammatory infiltration, vacuolation of liver cells, nuclear pyknosis, and fatty change than the controls. These findings highlight the potential role of metal mixtures in lipid metabolism with sex-dependent heterogeneity. More researches are needed to explore the underlying mechanisms.

Circ_ROBO2/miR-149 Axis Promotes the Proliferation and Migration of Human Aortic Smooth Muscle Cells by Activating NF-κB Signaling.

Atherosclerosis is the leading global cause of mortality. The occurrence of coronary artery disease (CAD) is regulated by a diversity of pathways, including circRNAs. However, the potential mechanisms of circRNAs in CAD remain unclear. Here, qRT-PCR was used to examine the expressions of miR-149 and circ_ROBO2. Their influences on cell proliferation, migration, and apoptosis were measured by CCK-8, trans-well, and flow cytometry assays, respectively. The protein levels of p-IκBα and NF-κB p65 were examined using western blot. The molecular interactions were validated using dual luciferase reporter and RNA pull-down assays. The expression patterns of circ_ROBO2 and miR-149 in CAD patients and PDGF-BB-treated human aortic smooth muscle cells (HASMCs) were upregulated and downregulated, respectively. Knockdown of circ_ROBO2 could markedly inhibit the capabilities of proliferation and migration, enhance the apoptotic rate, and suppress NF-κB signaling in PDGF-BB-treated HASMCs. Mechanistically, circ_ROBO2 acted as a sponge of miR-149 to activate TRAF6/NF-κB signaling. Rescue studies demonstrated that neither silencing miR-149 nor activation of NF-κB signaling obviously abolished the biological roles of circ_ROBO2 knockdown in PDGF-BB treated-HASMCs. This discovery elucidated a functional mechanism of circ_ROBO2 in CAD, suggesting that circRNAs serve a vital role in the progression of CAD.

Vascular smooth muscle cells activate PI3K/Akt pathway to attenuate myocardial ischemia/reperfusion-induced apoptosis and autophagy by secreting bFGF.

BACKGROUND: Vascular smooth muscle cells (VSMCs) has been reported to be implicated in atherosclerotic plaque instability and rupture. Recently, it has been demonstrated that VSMCs block the progression of cardiac remodeling and thus promoting cardiac function in a rat myocardial infarction model. However, the detailed molecular mechanism of how VSMCs contributes to recovery in myocardial ischemia/reperfusion remains not fully understood. METHODS: We have isolated, identified and cultured VSMCs from rats to co-culture with rat cardiomyocyte H9C2. To culture H9C2 cells under hypoxia, we utilized CoCl2-containing medium to culture for 8 h and then was replaced with normal media for additional 16 h. Cell viability was examined by MTT assay and apoptosis was determined by flow cytometry. Infarcted area of myocardial tissue was measured by TTC staining. RESULTS: VSMCs was shown to promote cell viability and inhibit apoptosis of H9C2 cells under hypoxia, which exhibited upregulated anti-apoptotic protein Bcl-2 and autophagy-related protein p62, whereas pro-apoptotic protein cleaved caspase-3 and the level of LC3II/LC3I were downregulated. Then, we confirmed VSMCs played the contributory role in cell viability of H9C2 under hypoxia by secreting bFGF, which exerted its function through PI3K/Akt pathway. Finally, in vivo, the results demonstrated that VSMCs transplantation contributed to recovery of myocardial ischemia. CONCLUSION: We determine that VSMCs promote recovery of infarcted cardiomyocyte through secretion of bFGF, which then activating PI3K/Akt pathway to inhibit apoptosis and autophagy. These findings provide more insights into the molecular mechanism underlying VSMCs contributing to recovery of myocardial I/R and facilitate developing therapeutical strategies for treating heart diseases.