Inserte, J. | bioRxiv Science

bioRxiv2025

CERIUM OXIDE NANOPARTICLES ATTENUATE THE PRO-ARRHYTHMIC EFFECT OF DIESEL EXHAUST PARTICLES IN ISOLATED RAT HEARTS BY REDUCING OXIDATIVE STRESS.

IntroductionEpidemiological studies suggest an association between air pollution and ventricular arrhythmias, with reactive oxygen species (ROS) playing a crucial role. However, the causal relationship and long-term effects remain uncertain, and the effectiveness of interventions aimed at reducing ROS requires further investigation. AimsTo evaluate the effects of chronic exposure to diesel exhaust particles (DEPs) on ventricular arrhythmogenesis, explore the underlying mechanisms, and assess the potential of cerium oxide nanoparticles (CeO2NP) as a ROS-detoxifying intervention. MethodsSprague-Dawley rats underwent intratracheal instillation of saline without or with DEPs (7.5 g/Kg for 1-3 weeks). Ventricular arrhythmia inducibility was then assessed in isolated hearts using a protocol of programmed electrical stimulation. Cardiac hypertrophy, collagen content, inflammation and oxidative stress were analyzed using histology, Western blot, RT-PCR, and measurement of malondialdehyde content. The potential protective effects of CeO2NP (0.5 mg/Kg/week, i.p.) were also tested. ResultsDEP exposure for 3 weeks increased the incidence and duration of sustained ventricular tachyarrhythmias (VTs), a finding that correlated with a moderate increase in interstitial collagen (from 3.11{+/-}0.12% in controls to 4.80{+/-}0.21% in DEP-exposed rats, p<0.001), and an early upregulation in the expression of collagen and other fibrotic and inflammatory markers. These effects associated with prolonged QRS complex and QTc intervals, and enhanced malondialdehyde content (356.7{+/-}21.2 vs. 455.3{+/-}17.2 mol/g tissue, p=0.0066) after 3 weeks. CeO2NP treatment reduced oxidative stress and myocardial fibrosis, reversed electrocardiographic changes and attenuated DEP-induced pro-arrhythmic effects. ConclusionDEP exposure increases the incidence and duration of sustained VTs, collagen deposition and oxidative stress in rats. Treatment with CeO2NP attenuate these effects, arising as a potential novel strategy to mitigate the deleterious effects of air pollution.

pharmacology and toxicology↗

bioRxiv2020

Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ after myocardial infarction

Macrophages produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. In this study, we demonstrated that cardiac macrophages increased expression of Mmp14 (MT1-MMP) 7 days post-MI. Specific macrophage-targeting of MT1-MMP (MT1-MMP{Delta}LysM mice) attenuates post-MI cardiac dysfunction, reduces fibrosis, and preserves the cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGF{beta}1 in macrophages, leading to paracrine SMAD2-mediated signaling in endothelial cells and endothelial-to-mesenchymal transition (EndMT). Post-MI MT1-MMP{Delta}LysM hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and MT1-MMP-deficient macrophages showed a reduced ability to induce EndMT in co-cultures with endothelial cells. Our results demonstrate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify macrophage MT1-MMP as a key regulator of this process. The identified mechanism has potential as a therapeutic target in ischemic heart disease.

immunology↗