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It is reported that oxidative stress homeostasis was involved in PM 2.5 -induced foam cell formation and progression of atherosclerosis, but the exact molecular mechanism is still unclear. Melatonin is an effective antioxidant that could reverse the cardiopulmonary injury. The main purpose of this study is to investigate the latent mechanism of PM 2.5 -triggered atherosclerosis development and the protective role of melatonin administration. Vascular Doppler ultrasound showed that PM 2.5 exposure reduced aortic elasticity in ApoE-/- mice. Meanwhile, blood biochemical and pathological analysis demonstrated that PM 2.5 exposure caused dyslipidemia, elicited oxidative damage of aorta and was accompanied by an increase in atherosclerotic plaque area; while the melatonin administration could effectively alleviate PM 2.5 -induced macrophage M1 polarization and atherosclerosis in mice. Further investigation verified that NADPH oxidase 2 (NOX2) and mitochondria are two prominent sources of PM 2.5 -induced ROS production in vascular macrophages. Whereas, the combined use of two ROS-specific inhibitors and adopted with melatonin markedly rescued PM 2.5 -triggered macrophage M1 polarization and foam cell formation by inhibiting NOX2-mediated crosstalk of Keap1/Nrf2/NF-κB and TLR4/TRAF6/NF-κB signaling pathways. Our results demonstrated that NOX2-mediated oxidative stress homeostasis is critical for PM 2.5 -induced atherosclerosis and melatonin might be a potential treatment for air pollution-related cardiovascular diseases. [Display omitted] • PM 2.5 exposure triggers macrophage M1 polarization and foam cell formation. • NOX2-mediated crosstalk of Keap1 and TLR4 pathway is critical for PM 2.5 -induced atherosclerosis. • Melatonin can alleviate PM 2.5 -triggered atherosclerosis via oxidative stress homeostasis. [ABSTRACT FROM AUTHOR]

Ambient air pollution is a leading cause of non-communicable disease in the world. PM2.5 has the potential to change the miRNAs profiles, which in turn causes cardiovascular effects. Hypoxia-inducible factor (HIF)-1 plays a critical role in the development of atherosclerosis. Yet, the possible role of miR-939-5p/HIF-1α in PM2.5-induced endothelial injury remains elusive. Therefore, the study aims to investigate the effects of miR-939-5p and HIF-1α on PM2.5-triggered endothelial injury. The results from immunofluorescence, qRT-PCR, LSCM, and western blot assays demonstrated that PM2.5 increased the levels of HIF-1α, inflammation and apoptosis in human aortic endothelial cells (HAECs). Yet, the inflammatory response and mitochondrial-mediated apoptosis pathway were effectively inhibited in HIF-1α knockdown HAECs lines. The expression of miR-939-5p was significantly down-regulated in HAECs after exposed to PM2.5. The luciferase reporter, qRT-PCR and western blot results demonstrated that miR-939-5p could directly targeted HIF-1α. And the miR-939-5p overexpression restricted PM2.5-triggered decreases in cell viability and increases in lactic dehydrogenase (LDH) activity, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and inflammation. In addition, miR-939-5p overexpression remarkably suppressed PM2.5-triggered BcL-2/Bax ratio reduction and Cytochrome C, Cleaved Caspase-9 and Cleaved Caspase-3 expression increase, revealed that miR-939-5p hampered PM2.5-induced endothelial apoptosis through mitochondrial-mediated apoptosis pathway. Our results demonstrated that PM2.5 increased the expression of HIF-1α followed by a pro-inflammatory and apoptotic response in HAECs. The protective effect of miR-939-5p on PM2.5-triggered endothelial cell injury by negatively regulating HIF-1α. miR-939-5p might present a new therapeutic target for PM2.5 induced endothelial injury. [ABSTRACT FROM AUTHOR]

Epidemiological evidence showed that the particulate matter exposure is associated with atherosclerotic plaque progression, which may be related to foam cell formation, but the mechanism is still unknown. The study was aimed to investigate the toxic effects and possible mechanism of PM 2.5 on the formation of macrophage foam cells induced by oxidized low density lipoprotein (ox-LDL). Results showed that PM 2.5 induced cytotoxicity by decreasing the cell viability and increasing the LDH level in macrophage foam cells. PM 2.5 aggravated the lipid accumulation in ox-LDL-stimulated macrophage RAW264.7 within markedly increasing level of intracellular lipid by Oil red O staining. The level of ROS increased obivously after co-exposure to PM 2.5 and ox-LDL than single exposure group. In addition, serious mitochondrial damage such as the mitochondrial swelling, cristae rupturing and disappearance were observed in macrophage foam cells. The loss of the mitochondrial membrane potential (MMP) further exacerbated the mitochondrial damage in PM 2.5 -induced macrophage foam cells. The apoptotic rate increased more severely via up-regulated protein level of Bax, Cyt C, Caspase-9, Caspase-3, and down-regulated that of Bcl-2, indicating that PM 2.5 activated the mitochondrial-mediated apoptosis pathway. In summary, our results demonstrated that PM 2.5 aggravated the lipid accumulation, mitochondrial damage and apoptosis in macrophage foam cells, suggesting that PM 2.5 was a risk factor of atherosclerosis progression. Image 1 • PM 2.5 aggravated the content of intracellular TC and lipid accumulation in macrophage foam cells. • PM 2.5 triggered the ROS generation and loss of MMP, resulted in mitochondrial damage. • PM 2.5 could accelerate the apoptosis via the Cyt C/Caspase-9/Caspase-3 pathway. [ABSTRACT FROM AUTHOR]