Faculty Bibliography

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

Cholesterol metabolism is tightly regulated at the cellular level. Here we show that miR-33, an intronic microRNA (miRNA) located within the gene encoding sterol-regulatory element-binding factor-2 (SREBF-2), a transcriptional regulator of cholesterol synthesis, modulates the expression of genes involved in cellular cholesterol transport. In mouse and human cells, miR-33 inhibits the expression of the adenosine triphosphate-binding cassette (ABC) transporter, ABCA1, thereby attenuating cholesterol efflux to apolipoprotein A1. In mouse macrophages, miR-33 also targets ABCG1, reducing cholesterol efflux to nascent high-density lipoprotein (HDL). Lentiviral delivery of miR-33 to mice represses ABCA1 expression in the liver, reducing circulating HDL levels. Conversely, silencing of miR-33 in vivo increases hepatic expression of ABCA1 and plasma HDL levels. Thus, miR-33 appears to regulate both HDL biogenesis in the liver and cellular cholesterol efflux

High density lipoprotein (HDL), an endogenous nanoparticle, transports fat throughout the body and is capable of transferring cholesterol from atheroma in the vessel wall to the liver. In the present study, we utilized HDL as a multimodal nanoparticle platform for tumor targeting and imaging via nonspecific accumulation and specific binding to angiogenically activated blood vessels. We reconstituted HDL (rHDL) with amphiphilic gadolinium chelates and fluorescent dyes. To target angiogenic endothelial cells, rHDL was functionalized with alphavbeta3-integrin-specific RGD peptides (rHDL-RGD). Nonspecific RAD peptides were conjugated to rHDL nanoparticles as a control (rHDL-RAD). It was observed in vitro that all 3 nanoparticles were phagocytosed by macrophages, while alphavbeta3-integrin-specific rHDL-RGD nanoparticles were preferentially taken up by endothelial cells. The uptake of nanoparticles in mouse tumors was evaluated in vivo using near infrared (NIR) and MR imaging. All nanoparticles accumulated in tumors but with very different accumulation/binding kinetics as observed by NIR imaging. Moreover, confocal microscopy revealed rHDL-RGD to be associated with tumor endothelial cells, while rHDL and rHDL-RAD nanoparticles were mainly found in the interstitial space. This study demonstrates the ability to reroute HDL from its natural targets to tumor blood vessels and its potential for multimodal imaging of tumor-associated processes.

Chronic kidney disease (CKD) accelerates cardiovascular disease. The mechanisms that explain this independent, excess risk associated with CKD have not been fully elucidated. OBJECTIVES: We propose that impaired regression of atherosclerosis in renal disease represents a novel risk factor for the heightened morbidity and mortality and resistance to treatment observed in patients with CKD. METHODS AND RESULTS: Using a transplant model to study atherosclerosis regression, we transplanted atheromatous aortic segments generated in Apolipoprotein E knock-out (ApoE(-/-)) mice, into either control or moderately uremic, normolipidemic, wild-type mice. In non-uremic mice, lesions regressed 55%, whereas lesions in uremic mice increased in size by 17% (p<0.01 for control vs. uremic). The lesions in uremic mice were also characterized by a greater presence of macrophages (36,300 microm(2) vs. 12,600 microm(2), p<0.01). This finding was despite upregulation of chemokine receptor 7 (CCR7), normally a migration factor, in uremic lesion macrophages. Gene expression analysis of lesion macrophages showed relative down-regulation of serum response factor (SRF) target genes in the uremic group, consistent with impaired CCR7 signaling. CONCLUSION: Moderate kidney disease inhibits regression of atherosclerosis in a mouse transplant model. This inhibition may be a result of impaired CCR7 signaling

Immune and inflammatory cells play a critical role in the pathogenesis of atherosclerotic plaques. We have demonstrated that A2ARs inhibit foam cell formation and stimulate production of ABCA1, the primary transporter of lipoproteins. We asked whether the effects of A2ARs on foam cell formation in vitro are mediated by transporters involved in reverse cholesterol transport, ABCA1 and ABCG1. Foam cells were generated from THP-1 cells by incubation with 100 nM PMA for 2 days and incubated with acLDL (50 mug/mL) plus IFN-gamma (500 U/mL) +/- A2AR agonist CGS-21680 (1 muM). Radiolabeled cholesterol (0.2 muCi/ml) was added to cells, and efflux was measured using a liquid scintillation counter. Lentiviral siRNA infection markedly reduces ABCA1 or ABCG1 mRNA in THP-1 cells. Despite diminished ABCG1 expression (KD), CGS-21680 inhibits foam cell formation (81+5% inhibition; P<0.0001 vs. IFN-gamma alone; n=3) but has no effect on foam cell formation in ABCA1 KD cells (5+3% inhibition; P<0.85 vs. IFN-gamma alone; n=3). The A2A agonist increases apoA-I-mediated cholesterol efflux nearly twofold in THP-1-derived macrophages (from 9.5% to 17.5+2.5% [3H]-cholesterol efflux; P<0.0090 vs. control; n=3) but not in ABCA1 KD cells. Activation of Epac, a signaling molecule downstream of the A2AR, increased ABCA1 (23+5%; P<0.0007 vs. control; n=3) and phospho-ABCA1 (13+5%; P<0.0003 vs. control; n=3) protein. These results demonstrate that A2AR occupancy diminishes foam cell formation by stimulating increased reverse cholesterol transport via ABCA1

Lipoproteins, natural nanoparticles, have a well-recognized biological role and are highly suitable as a platform for delivering imaging agents. The ease with which both the exterior and interior of the particles can be modified permits the creation of multifunctional nanoparticles for imaging as well as the delivery of therapeutics. Importantly, their endogenous nature may make them biocompatible and biodegradable and allows them to avoid the recognition of the reticuloendothelial system. In particular, high-density lipoproteins (HDL) are of interest, because of their small size they can easily cross the endothelium and penetrate the underlying tissue. We summarize here the progress in establishing HDL as a vector for delivering a variety of diagnostically active materials to vulnerable atherosclerotic plaques in mouse models of atherosclerosis. By loading various types of image-enhancing compounds into either the core or surface of HDL, they can be visualized by different imaging modalities (MRI, CT, optical). By rerouting of HDL away from plaque macrophages, imaging of biological processes in diseases besides atherosclerosis may also be achieved

Patients from the Indian subcontinent have a distinct cardiovascular risk profile with profound health consequences. South Asians tend to develop more severe coronary artery disease at a younger age, and may also suffer from earlier myocardial infarction and heart failure. The genesis of this risk is multi-factorial. One important culprit is increased insulin resistance, possibly due to recently identified genetic polymorphisms. Another possible explanation is subclinical inflammation and a prothrombotic environment, as evidenced by increased levels of homocysteine, plasminogen activator inhibitor-1, and fibrinogen. The lipid profile of South Asians may play a role, as this population is known to have elevated levels of lipoprotein (a), as well as lower levels of HDL. In addition, this HDL may be dysfunctional, as this population may have a higher prevalence of low levels of HDL2b, as well as an increased preponderance of smaller HDL. Current guidelines for primary and secondary prevention have not reflected our growing insight into the unique characteristics of the South Asian population, and may need to evolve to reflect our knowledge