Xiaoxu Zhou

Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF). The mechanisms underlying DM-associated AF are unclear. AF and DM are both related to inflammation. We investigated whether DM-associated inflammation contributed to AF risk. Mice were fed with high-fat diet to induce type II DM and were subjected to IL-1β antibodies, macrophage depletion by clodronate liposomes, a mitochondrial antioxidant (mitoTEMPO), or a cardiac ryanodine receptor 2 (RyR2) stabilizer (S107). All tests were performed at 36–38 weeks of age. DM mice presented with increased AF inducibility, enhanced mitochondrial reactive oxygen species (mitoROS) generation, and activated innate immunity in the atria, as evidenced by enhanced monocyte chemoattractant protein-1 (MCP-1) expression, macrophage infiltration, and IL-1β levels. Signs of aberrant RyR2 Ca ²⁺ leak were observed in the atria of DM mice. IL-1β neutralization, macrophage depletion, and exposure to mitoTEMPO and S107 significantly ameliorated the AF vulnerability in DM mice. Atrial overexpression of MCP-1 increased AF occurrence in normal mice through the same mechanistic signaling cascade as observed in DM mice. In conclusion, macrophage-mediated IL-1β contributed to DM-associated AF risk through mitoROS modulation of RyR2 Ca ²⁺ leak.

Summary: Oxidative stress plays an important role in atherosclerosis, a vascular disease with high morbidity and mortality. The ETS domain‐containing protein ELK1 is an oxidative stress‐sensitive factor modulated by the extracellular signal‐regulated kinase (ERK) 1/2 pathway. However, the role of ELK1 in the prevention of atherosclerosis by pravastatin remains unclear. In the present study, male apolipoprotein E‐knockout (apoE^−/−) mice fed a diet containing 1.25% cholesterol (w/w) were divided into two groups, one treated with pravastatin (80 mg/kg, 2‐2.4 mg/mouse per day) for 8 weeks and the other not. Male C57BL/6J mice fed with a normal diet were used as a control group. Human umbilical vein endothelial cells (HUVEC) were cultured and treated with pravastatin (10 μmol/L) for 18 hours before testing for the presence or absence of 100 μmol/L H₂O₂ (24 hours). Examination of pathological sections from mice aortas revealed that pravastatin treatment almost prevented atherosclerotic plaque formation. Pravastatin also inhibited increases in serum and aortic levels of oxidized low‐density lipoprotein and aortic malondialdehyde levels and decreases in aortic reduced glutathione, and the activities of superoxide dismutase, catalase and glutathione peroxidase. H₂O₂‐induced increases in reactive oxygen species in HUVECs were reversed by pravastatin by 48%. Pravastatin blocked the phosphorylation of ELK1 and ERK1/2 proteins and reduced mRNA levels of early growth response 1, a known atherogenic transcription factor upregulated by the ROS/ERK/ELK1 pathway, in mice. In conclusion, pravastatin attenuates the action of ELK1 induced by oxidative stress to prevent atherosclerosis, which is dependent partly on modulation of ERK1/2 signalling.