Simoglou Karali, C. | bioRxiv Science

bioRxiv2025

Hypercholesterolaemia promotes epigenetic memory in hematopoietic stem cells that persists after lipid lowering and causes systemic immunometabolic dysfunction mediated by macrophage metabolic reprogramming

In patients with atherosclerotic cardiovascular disease (ASCVD) lowering LDL cholesterol (LDL-C) reduces the risk of adverse cardiovascular events. However, these patients remain at continued risk of adverse cardiovascular events despite achieving optimal LDL-C lowering. We hypothesised that this residual risk is mediated by epigenetic programming of haematopoietic stem cells (HSC) which persists after cholesterol levels are lowered and results in sustained effects on innate immune cell metabolism, that is not resolved by cholesterol lowering. We found that exposure to high cholesterol (HC) in vivo induced long-term metabolic changes in macrophages differentiated ex vivo from bone marrow, leading to a pro-inflammatory profile; these changes persisted in vivo despite cholesterol lowering. HSC from HC mice had altered chromatin accessibility that persisted after cholesterol lowering and was also present in bone marrow monocytes and tissue resident macrophages. HC provoked RUNX1-dependent downregulation of stearoyl-CoA desaturase (SCD) which reduced mono-unsaturated fatty acid (MUFA) availability for OxPhos in murine and human monocytes and macrophages. Supplementation with MUFA restored OxPhos capacity and promoted a shift towards a less pro-inflammatory macrophage phenotype in HC-trained BMDM. Bone marrow chimera and lineage tracking studies revealed that prior exposure of HSC to HC conferred adverse systemic metabolic effects on normocholesterolemic mice, with increased adipose tissue mass and increased migration of macrophages derived from HC-exposed HSC into adipose tissue, resulting in increased adipose tissue inflammation and systemic glucose intolerance. These findings indicate that HC results in long-lasting immuno-epigenetic memory in HSC which is refractory to lipid lowering, and provide strong evidence that exposure to HC can have prolonged consequences that require new therapeutic approaches, beyond cholesterol lowering.

immunology↗

bioRxiv2024

Rapamycin Treatment Reduces Brain Pericyte Constriction in Ischemic Stroke

The contraction and subsequent death of brain pericytes may play a role in microvascular no-reflow following the re-opening of an occluded artery during ischemic stroke. Mammalian target of rapamycin (mTOR) inhibition has been shown to reduce motility/contractility of various cancer cell lines and reduce neuronal cell death in stroke. However, the effects of mTOR inhibition on brain pericyte contraction and death during ischemia have not yet been investigated. Cultured pericytes exposed to simulated ischemia for 12 hours in vitro contracted after less than 1 h, which was about 7h prior to cell death. Rapamycin significantly reduced the rate of pericyte contraction during ischemia, however, it did not have a significant effect on pericyte viability at any time point. Rapamycin appeared to reduce pericyte contraction through a RhoA-dependent pathway, independent of changes in intracellular calcium. Using a mouse model of middle cerebral artery occlusion, rapamycin significantly increased the diameter of capillaries underneath pericytes and increased the number of open capillaries 30 minutes following recanalization. Our findings suggest rapamycin may be a useful adjuvant therapeutic to reduce pericyte contraction and improve cerebral reperfusion post-stroke.

neuroscience↗