Faculty Bibliography

Atherosclerosis is an inflammatory disease causing great morbidity and mortality in the Western world. To increase the anti-inflammatory action and decrease adverse effects of glucocorticoids (PLP), a nanomedicinal liposomal formulation of this drug (L-PLP) was developed and intravenously applied at a dose of 15 mg/kg PLP to a rabbit model of atherosclerosis. Since atherosclerosis is a systemic disease, emerging imaging modalities for assessing atherosclerotic plaque are being developed. (18)F-Fluoro-deoxy-glucose positron emission tomography and dynamic contrast enhanced magnetic resonance imaging, methods commonly used in oncology, were applied to longitudinally assess therapeutic efficacy. Significant anti-inflammatory effects were observed as early as 2 days that lasted up to at least 7 days after administration of a single dose of L-PLP. No significant changes were found for the free PLP treated animals. These findings were corroborated by immunohistochemical analysis of macrophage density in the vessel wall. In conclusion, this study evaluates a powerful two-pronged strategy for efficient treatment of atherosclerosis that includes nanomedical therapy of atherosclerotic plaques and the application of noninvasive and clinically approved imaging techniques to monitor delivery and therapeutic responses. Importantly, we demonstrate unprecedented rapid anti-inflammatory effects in atherosclerotic lesions after the nanomedical therapy

We have previously shown that mouse atherosclerosis regression involves monocyte-derived (CD68+) cell emigration from plaques and is dependent on the chemokine receptor CCR7. Concurrent with regression, mRNA levels of the gene encoding LXRalpha are increased in plaque CD68+ cells, suggestive of a functional relationship between LXR and CCR7. To extend these results, atherosclerotic Apoe-/- mice sufficient or deficient in CCR7 were treated with an LXR agonist, resulting in a CCR7-dependent decrease in plaque CD68+ cells. To test the requirement for LXR for CCR7-dependent regression, we transplanted aortic arches from atherosclerotic Apoe-/- mice, or from Apoe-/- mice with BM deficiency of LXRalpha or LXRbeta, into WT recipients. Plaques from both LXRalpha and LXRbeta-deficient Apoe-/- mice exhibited impaired regression. In addition, the CD68+ cells displayed reduced emigration and CCR7 expression. Using an immature DC line, we found that LXR agonist treatment increased Ccr7 mRNA levels. This increase was blunted when LXRalpha and LXRbeta levels were reduced by siRNAs. Moreover, LXR agonist treatment of primary human immature DCs resulted in functionally significant upregulation of CCR7. We conclude that LXR is required for maximal effects on plaque CD68+ cell expression of CCR7 and monocyte-derived cell egress during atherosclerosis regression in mice

PURPOSE: To investigate the potential of spectral computed tomography (CT) (popularly referred to as multicolor CT), used in combination with a gold high-density lipoprotein nanoparticle contrast agent (Au-HDL), for characterization of macrophage burden, calcification, and stenosis of atherosclerotic plaques. MATERIALS AND METHODS: The local animal care committee approved all animal experiments. A preclinical spectral CT system in which incident x-rays are divided into six different energy bins was used for multicolor imaging. Au-HDL, an iodine-based contrast agent, and calcium phosphate were imaged in a variety of phantoms. Apolipoprotein E knockout (apo E-KO) mice were used as the model for atherosclerosis. Gold nanoparticles targeted to atherosclerosis (Au-HDL) were intravenously injected at a dose of 500 mg per kilogram of body weight. Iodine-based contrast material was injected 24 hours later, after which the mice were imaged. Wild-type mice were used as controls. Macrophage targeting by Au-HDL was further evaluated by using transmission electron microscopy and confocal microscopy of aorta sections. RESULTS: Multicolor CT enabled differentiation of Au-HDL, iodine-based contrast material, and calcium phosphate in the phantoms. Accumulations of Au-HDL were detected in the aortas of the apo E-KO mice, while the iodine-based contrast agent and the calcium-rich tissue could also be detected and thus facilitated visualization of the vasculature and bones (skeleton), respectively, during a single scanning examination. Microscopy revealed Au-HDL to be primarily localized in the macrophages on the aorta sections; hence, the multicolor CT images provided information about the macrophage burden. CONCLUSION: Spectral CT used with carefully chosen contrast agents may yield valuable information about atherosclerotic plaque composition

Omega-3 fatty acids, which are found abundantly in fish oil, are increasingly being used in the management of cardiovascular disease. It is clear that fish oil, in clinically used doses (typically 4 g/d of eicosapentaenoic acid and docosahexaenoic acid) reduce high triglycerides. However, the role of omega-3 fatty acids in reducing mortality, sudden death, arrhythmias, myocardial infarction, and heart failure has not yet been established. This review will focus on the current clinical uses of fish oil and provide an update on their effects on triglycerides, coronary artery disease, heart failure, and arrhythmia. We will explore the dietary sources of fish oil as compared with drug therapy, and discuss the use of fish oil products in combination with other commonly used lipid-lowering agents. We will examine the underlying mechanism of fish oil's action on triglyceride reduction, plaque stability, and effect in diabetes, and review the newly discovered anti-inflammatory effects of fish oil. Finally, we will examine the limitations of current data and suggest recommendations for fish oil use

The mechanism of lipoprotein lipase (LPL) transport from muscle and fat cells to the luminal (apical) surface of capillaries, where it hydrolyses lipoprotein triglycerides, has remained undefined. In this issue, Davies et al. (2010) report that GPIHBP1 is required for LPL transcytosis from the basolateral to apical capillary endothelial surface