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Age is undoubtedly a major risk factor for heart disease. However, the reason for this is not entirely clear. In the course of our investigation into the mechanism of radiation-induced cardiovascular disease, we made several unexpected findings that inform us on this question. We observed that human coronary endothelial cells, while being able to initiate repair of radiation-induced DNA damage, often fail to complete the repair and become senescent. Such radiation-induced cellular aging occurs through a mutation-independent route. Endothelial cells that aged naturally through replication or as a result of radiation exhibited indistinguishable characteristics. The promoter regions of the CD44 gene in aging endothelial cells become demethylated, and the proteins are highly expressed on the cell surface, making the cells adhesive for monocytes. Adhesion is a cardinal feature that recruits monocytes to the endothelium, allowing them to infiltrate the vessel wall and initiate atherosclerosis. The epigenetic activation of CD44 expression is particularly significant as it causes persistent elevated CD44 protein expression, making senescent endothelial cells chronically adhesive. In addition to understanding why cardiovascular disease increases with age, these observations provide insights into the puzzling association between radiation and cardiovascular disease and highlight the need to consider premature aging as an additional risk of radiation to human health.

Adhesion and proliferation of vascular endothelial cells are important parameters in the endothelialization of biomedical devices for vascular applications. Endothelialization is a complex process affected by endothelial cells and their interaction with the extracellular microenvironment. Although numerous approaches are taken to study the influence of the external environment, a systematic investigation of the impact of an engineered microenvironment on endothelial cell processes is needed. This study aims to investigate the influence of topography, initial cell seeding density, and collagen coating on human umbilical vein endothelial cells (HUVECs). Utilizing the MultiARChitecture (MARC) chamber, the effects of various topographies on HUVECs are identified, and those with more prominent effects were further evaluated individually using the MARC plate. Endothelial cell marker expression and monocyte adhesion assay are examined on the HUVEC monolayer. HUVECs on 1.8 μm convex and concave microlens topographies demonstrate the lowest cell adhesion and proliferation, regardless of initial cell seeding density and collagen I coating, and the HUVEC monolayer on the microlens shows the lowest monocyte adhesion. This property of lens topographies would potentially be a useful parameter in designing vascular biomedical devices. The MARC chamber and MARC plate show a great potential for faster and easy pattern identification for various cellular processes.

Chronic inflammatory diseases including atherosclerosis are major causes of morbidity and mortality worldwide. However, the factors, which trigger processes that determine the outcome of an inflammatory response, are still poorly understood. Accumulating evidence suggests that certain lipid oxidation products, such as oxidized phospholipids (OxPL), may represent endogenously formed factors that are capable of triggering vascular inflammation. This review will address important questions regarding mechanisms involved in acute and chronic inflammation, and discuss the role of OxPL as key players in triggering the inflammatory response in atherosclerosis. Better understanding of how OxPL contribute to vascular inflammation should lead to new strategies in the treatment of chronic inflammatory disorders.

Thiazolidinediones (TZDs), potent peroxisome proliferator-activated receptor γ ligands, have been shown to improve endothelial function in vascular diseases. We investigated the effects of pioglitazone, a TZD, on monocyte–endothelial interaction under flow and found that pretreatment (20 μmol/l, 48 h) significantly reduced U937 adhesion to human umbilical vein endothelial cells. Integrin expression was not altered, however, the activation of RhoA GTPase was significantly reduced after treatment. Further, pioglitazone treatment significantly reduced phosphorylation of focal adhesion kinase (FAK) at 925Y, but not at 397Y, suggesting a specific role in FAK-dependent signaling. These results indicate a novel anti-inflammatory role for this compound.

Cardiovascular disease (CVD) incidence is higher in Type 1 diabetic (T1D) patients. Along with hyperglycemia, T1D is associated with hyperketonemia, a condition with elevated blood levels of acetoacetate (AA) and 3-β-hydroxybutyrate (BHB). It is not known whether hyperketonemia per se contributes to the excess CVD in T1D. This study investigates the hypothesis that ketones upregulate NADPH oxidases (NOX) and ROS and therby increase monocyte-endothelial adhesion. HUVEC were treated with AA or BHB (0-8 mM) ± high-glucose (25 mM) for 24 h. Results show that AA, but not BHB, increased ROS production, NOX activity, and NOX4 expression in HUVEC. Pretreatment with DPI (20 μM , inhibitor of NOX) abolished the effect of AA on ROS production. This suggests that AA effect on ROS production is mediated through the NOX. To further examine the role of NOX, we determined the effect of ketones in NOX4 knockdown (KD) HUVEC. There were significantly lower levels of ROS (65% vs. 20%), ICAM-1 (42% vs. 23%), and monocyte adhe...