It's reticulated: the liver at the heart of atherosclerosis

Abstract

Platelets play a critical role in both the initiation and progression of atherosclerosis, and even more so in the ensuing atherothrombotic complications. Low-dose aspirin remains the mainstay of antiplatelet therapy in high-risk patients by reducing the risk of myocardial ischemia, stroke or death due to cardiovascular disease. However, antiplatelet therapies lose their efficacy in people with diabetes mellitus, increasing the risk of future atherothrombotic events. The molecular mechanisms that promote platelet hyperactivity remain unclear but could be due to glycation-induced conformational changes of platelet membranes resulting in impaired aspirin entry or less-efficient acetylation/compensatory increase in COX-2 expression in newborn platelets. Emerging evidence from our laboratory and elsewhere suggest that enhanced platelet turnover (thrombopoiesis), particularly the production of immature reticulated platelets from the bone marrow, could contribute to atherosclerotic complications. We have identified a major role for neutrophil-derived S100A8/A9, a damage-associated molecular pattern, in driving reticulated thrombopoiesis by directly interacting with its receptors on Kupffer cells in the liver. In this review, we discuss the role of hepatic inflammation in driving reticulated platelet production and suggest potential targets to control their production, improve efficacy of current antiplatelet therapies and reduce the risk of atherothrombotic complications.

Impact of Metabolic Activity of Vertebra and Amygdala on Stroke Recurrence: A Prospective Cohort Study

“…Liver is a vital organ for cholesterol homeostasis and protein synthesis regulating inflammation and coagulation cascade, and several observational studies have reported that nonalcoholic fatty liver disease or combined liver fibrosis is associated with subclinical atherosclerosis and vascular event. 16,17 Patients with stroke with an increased FDG uptake in the vertebrae had more frequent stroke recurrence. Studies from coronary artery disease patients have found that increased FDG uptake in the vertebrae is associated with elevated serum C-reactive protein, arterial FDG uptake, and future vascular 6 However, the The Kaplan-Meier survival curve analysis demonstrates that patients with elevated FDG uptake in the vertebral body (red line, cutoff of >1.13) had a shorter stroke recurrence-free survival (log-rank test, P=0.009, A), and overall vascular events and death-free survival (log-rank test, P=0.016, B) than those with a low vertebral FDG uptake (blue line).…”

“…Liver is a vital organ for cholesterol homeostasis and protein synthesis regulating inflammation and coagulation cascade, and several observational studies have reported that nonalcoholic fatty liver disease or combined liver fibrosis is associated with subclinical atherosclerosis and vascular event. 16,17…”

Khdc3 Regulates Metabolism Across Generations in a DNA-Independent Manner

“…Global transcriptome analysis of Khdc3-null oocytes revealed significant dysregulation of genes important in metabolic processes regulated by the liver, especially the metabolism of lipids (atherosclerosis, PPAR signaling, and pantothenate and CoA metabolism) and of carbohydrates (glycolysis/gluconeogenesis, and fructose and mannose metabolism) (Fig. 1A) (19)(20)(21)(22). Despite the abnormal expression of metabolic genes in the Khdc3-null oocyte, this gene is only expressed in female reproductive tissue, with no detectable expression in the liver and minimal expression in other metabolic tissues such as adipose or pancreas (Fig.…”

Xinnaokang improves cecal microbiota and lipid metabolism to target atherosclerosis

“…3b,c). Dynamic changes in liver, very LDL content and hepatic steatosis are the main events affecting atherosclerosis (Fisher 2016;Muhammad et al 2018;Nagareddy et al 2018). Typically, lower-density lipids activate intracellular pathways to increase local and systemic inflammation, monocyte adhesion, endothelial cell dysfunction and apoptosis, and smooth muscle cell proliferation, leading to foam cell recruitment and atherosclerotic plaque formation (Helkin et al 2016).…”