Faculty Bibliography

OBJECTIVE:Exosomes are small secreted membrane vesicles formed in the late endocytic compartments by inward budding. Interest in these extracellular vesicles and their role in atherosclerosis is growing, as they can affect multiple cellular processes that lead to lipid overload, cytokine secretion and cellular adhesion. Exosomes protect and transport lipids, proteins, and RNAs, fostering intercellular communication among different cell types involved in atherogenesis such as macrophages, endothelium and smooth muscle. Their molecular composition reflects their cell type of origin, but they share attributes because they are enriched in proteins of their endosomal source. CONCLUSION/CONCLUSIONS:This review will describe the current state of our knowledge of exosome involvement in the development of atherosclerosis. The transfer of signaling molecules, lipids, mRNAs, and microRNAs via exosomes with effects on monocyte and macrophage cholesterol metabolism, endothelial cell and platelet activation and smooth muscle proliferation will be discussed. Finally, therapeutic potential of exosomes and clinical application will be explored.

Resveratrol is a bioactive molecule used in dietary supplements and herbal medicines and consumed worldwide. Numerous investigations by our group and others have indicated cardioprotective and anti-inflammatory properties of resveratrol. The present study explored potential atheroprotective actions of resveratrol on cholesterol efflux in cultured human macrophages exposed to plasma from systemic lupus erythematosus (SLE) patients. These results were confirmed in ApoE(-/-)Fas(-/-) double knockout mice, displaying a lupus profile with accelerated atherosclerosis. Resveratrol treatment attenuated atherosclerosis in these mice. THP-1 human macrophages were exposed to 10% pooled or individual plasma from patients who met diagnostic criteria for SLE. Expression of multiple proteins involved in reverse cholesterol transport (ABCA1, ABCG1, SR-B1, and cytochrome P450 27-hydroxylase) was assessed using QRT-PCR and Western blotting techniques. Ten-week-old ApoE(-/-)Fas(-/-) double knockout mice (n = 30) were randomly divided into two equal groups of 15, one of which received 0.01% resveratrol for 10 consecutive weeks. Atherosclerosis progression was evaluated in murine aortas. Bone marrow-derived macrophages (BMDM) were cultured and expression of cholesterol efflux proteins was analyzed in each group of mice. Our data indicate that inhibition of cholesterol efflux by lupus plasma in THP-1 human macrophages is rescued by resveratrol. Similarly, administration of resveratrol in a lupus-like murine model reduces plaque formation in vivo and augments cholesterol efflux in BMDM. This study presents evidence for a beneficial role of resveratrol in atherosclerosis in the specific setting of SLE. Therefore, resveratrol may merit investigation as an additional resource available to reduce lipid deposition and atherosclerosis in humans, especially in such vulnerable populations as lupus patients.

BACKGROUND: Leptin, an adipocyte-derived circulating cytokine that signals nutritional status, may play a role in the development of psoriasis and its associated systemic diseases. Patients with psoriasis have significantly decreased serum leptin levels compared with controls. AIM: To investigate the effect of two commonly used anti-psoriatic biologic drugs, adalimumab and ustekinumab, on leptin and leptin receptor expression in human macrophages. METHODS: THP-1 differentiated macrophages were cultured under the following conditions: (i) untreated control, (ii) adalimumab 5 mug/mL, (iii) ustekinumab 1 mug/mL and (iv) ustekinumab 5 mug/mL. Expression of leptin and leptin receptors were measured using real-time quantitative PCR and immunoblotting techniques. RESULTS: The presence of either adalimumab or ustekinumab in growth medium significantly upregulated expression of leptin receptor in THP-1 human macrophages to 1.98 +/- 0.47 and 2.09 +/- 0.24, respectively (n = 3, P < 0.01) vs. 1.12 +/- 0.19 for untreated control cells. However, only ustekinumab at a concentration of 5 mug/mL augmented expression of leptin to 1.99 +/- 0.56 (n = 3, P < 0.01) vs. control untreated cells. CONCLUSIONS: Enhanced leptin and leptin receptor expression in macrophages exposed to therapeutic levels of ustekinumab suggest a novel immunomodulatory mechanism for this biologic drug. Further mechanistic studies may yield targeted treatment using the leptin pathway, which could reduce the common obesity-related complications of psoriasis while alleviating symptoms and improving prognosis.