Roles of thromboxane A2 and prostacyclin in the development of atherosclerosis in apoE-deficient mice

Abstract

Production of thromboxane (TX) A 2 and PG I 2 /prostacyclin (PGI 2 ) is increased in patients with atherosclerosis. However, their roles in atherogenesis have not been critically defined. To examine this issue, we cross-bred atherosclerosis-prone apoE-deficient mice with mice deficient in either the TXA receptor (TP) or the PGI receptor (IP). Although they showed levels of serum cholesterol and triglyceride similar to those of apoE-deficient mice, apoE -/-TP -/-mice exhibited a significant delay in atherogenesis, and apoE -/-IP -/-mice exhibited a significant acceleration in atherogenesis compared with mice deficient in apoE alone. The plaques in apoE -/-IP -/-mice showed partial endothelial disruption and exhibited enhanced expression of ICAM-1 and decreased expression of platelet endothelial cell adhesion molecule 1 (PECAM-1) in the overlying endothelial cells compared with those of apoE -/-TP -/-mice. Platelet activation with thrombin ex vivo revealed higher and lower sensitivity for surface P-selectin expression in platelets of apoE -/-IP -/-and apoE -/-TP -/-mice, respectively, than in those of apoE -/-mice. Intravital microscopy of the common carotid artery revealed a significantly greater number of leukocytes rolling on the vessel walls in apoE -/-IP -/-mice than in either apoE -/-TP -/-or apoE -/-mice. We conclude that TXA 2 promotes and PGI 2 prevents the initiation and progression of atherogenesis through control of platelet activation and leukocyte-endothelial cell interaction.

The Apoe-/- Mouse PhysioLab® Platform: A Validated Physiologically-based Mathematical Model of Atherosclerotic Plaque Progression in the Apoe-/- Mouse

“…Virtual mice were considered internally validated if their simulated plaque progression was within the range reported in response to a range of stimuli such as chow diet, high fat diet, and ezetimibe treatment (see Supplemental Table 3). Moreover, simulated plaque progression rates for the cohort were consistent with observations in key Apoe -/-double knockout (PGI 2 , TXA 2 , and superoxide) studies [23,24]. Validated virtual mice exhibited also cholesterol profiles consistent with those observed experimentally in our laboratories.…”

“…Therefore, we assigned prevalence weights to individual mice such that the cohort matched the mean and 95% confidence interval of the 3 month experimental total cholesterol data from a calibration dataset while considering three scenarios of baseline plaque progression, Figure 5c (right). Lastly, upon simulated reductions in PGI2, TXA2, and superoxide, the virtual mouse cohort exhibited responses for plaque progression consistent with experimental data [23,24], thereby providing further confidence in the modeled physiology as these interventions are mechanistically distinct, Figure 5d.…”

Hypertensive stretch regulates endothelial exocytosis of Weibel-Palade bodies through VEGF receptor 2 signaling pathways

“…Immunohistological and intravital studies were performed 2 h after operation. For intravital microscopy, 0.1 mg/ ml Rhodamine 6G was injected to label leukocytes [34]. Adhered leukocytes were counted if they remained stationary for more than 20 s. We counted the number of leukocyte adhering in the artery per microscope field (100×) and presented the results as the number of leukocytes observed per field per minute.…”

Histamine Directly and Synergistically with Lipopolysaccharide Stimulates Cyclooxygenase-2 Expression and Prostaglandin I2 and E2 Production in Human Coronary Artery Endothelial Cells

“…PGI 2 is an antithrombotic and vasodilator molecule that can decrease vascular remodeling and cholesterol uptake (51,52). This is particularly evident from the fact that disruption of the prostacyclin receptor gene leads to increased intimamedium ratio in response to vascular injury and promotes initiation and progression of atherosclerosis in hyperlipidemic mouse (53,54), suggesting a protective role for prostacyclin in vascular remodeling. TXA 2 , in contrast, is a prothrombotic and vasoconstricting agent, and enhances vascular remodeling (51,52).…”