👤 Anita van Nieuwkoop-van Straalen

The selective cholesteryl ester transfer protein (CETP) inhibitor obicetrapib is in clinical evaluation for dyslipidemia and cardiovascular risk reduction. This study investigated how obicetrapib alone and with ezetimibe reduces non-HDL-C, affects atherosclerotic lesion progression, and regression when added to background atorvastatin intervention. APOE∗3-Leiden.CETP mice received a Western-type diet (WTD) or this diet supplemented with obicetrapib, ezetimibe, or both. After 8 weeks, all interventions reduced non-HDL-C levels (obicetrapib: -53%; ezetimibe: -19%; combination: -75%). Obicetrapib mono and combination treatment blocked CETP activity (-99% and -98%), thereby increasing HDL-C levels (+286% and +256%). Very low-density lipoprotein (VLDL) cholesterol production was not affected, while obicetrapib and the combination with ezetimibe increased VLDL clearance (plasma half-life [ Show less

Atherosclerosis is the major cause of cardiovascular disease. This study evaluated the effect of lipid lowering using a novel peptide inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) and a monoclonal antibody against angiopoietin-like 3 (evinacumab), either alone or in combination in APOE∗3-Leiden.CETP mice fed a Western diet. Effects on body weight, plasma lipids, atherosclerotic lesion size, severity, composition, and morphology were assessed. Treatment with PCSK9 inhibitory peptide significantly decreased both cholesterol and triglycerides (-69% and -68%, respectively). Similar reductions were seen in evinacumab-treated mice (-44% and -55%, respectively). The combination of evinacumab and PCSK9 inhibitory peptide lowered these levels to a larger extent than evinacumab alone (cholesterol: -74%; triglycerides: -81%). Reductions occurred in non-HDL-C without changes in HDL-C. Atherosclerotic lesion size was significantly reduced in all treatment groups compared to vehicle controls (evinacumab: -72%; PCSK9 inhibitory peptide: -97%; combination: -98%). Similarly, all interventions improved atherosclerotic lesion severity, with more undiseased segments and fewer severe lesions. Evaluation of the composition of severe atherosclerotic plaques revealed significant improvement in lesion stability in mice treated with both evinacumab and PCSK9 inhibitory peptide, attributable to decreased macrophage content and increased collagen content. Additionally, evaluation of lipid concentrations in cynomolgus monkeys revealed the beneficial effects of the PCSK9 inhibitory peptide on total cholesterol and LDL-C levels. Treatment with a novel PCSK9 inhibitory peptide alone or with evinacumab shows great potential to reduce and stabilize atherosclerotic lesions. Show less

Microplastics can enter the human body via direct body contact or the food chain, increasing the likelihood of adverse impacts on pregnancy and fetal development. We investigated the potential effects and modes of action of polystyrene nanoplastics (PS-NPs) in placenta and fetus using mice as a model species. Maternal PS-NP exposure (100 nm; 1 and 10 mg/L) via drinking water induced a significant decline in fetal weights at the higher exposure concentration. Abnormal morphologies of cells in the placenta and fetus were observed after exposure. For the placenta, transcriptomic analyses indicated that PS-NPs significantly disturbed cholesterol metabolism and complement and coagulation cascades pathways. Metabolomics showed appreciable metabolic disorders, particularly affecting sucrose and daidzein concentrations. For the fetal skeletal muscle, transcriptomics identified many significantly regulated genes, involving muscle tissue development, lipid metabolism, and skin formation. Transcriptomic analysis of the placenta and fetal skeletal muscle at the high PS-NP concentration showed that APOA4 and its transcriptional factors, facilitating cholesterol transportation, were significantly regulated in both tissues. Our study revealed that PS-NPs caused fetal growth restriction and significantly disturbed cholesterol metabolism in both placenta and fetus, offering new insights into the mechanisms underlying the placental and fetal effects in mice exposed to PS-NPs. Show less