Protective role of chaperone-mediated autophagy against atherosclerosis

Chaperone-mediated autophagy (CMA) contributes to regulation of energy homeostasis by timely degradation of enzymes involved in glucose and lipid metabolism. Here, we report reduced CMA activity in vascular smooth muscle cells and macrophages in murine and human arteries in response to atherosclerotic challenges. We show that in vivo genetic blockage of CMA worsens atherosclerotic pathology through both systemic and cell-autonomous changes in vascular smooth muscle cells and macrophages, the two main cell types involved in atherogenesis. CMA deficiency promotes dedifferentiation of vascular smooth muscle cells and a proinflammatory state in macrophages. Conversely, a genetic mouse model with up-regulated CMA shows lower vulnerability to proatherosclerotic challenges. We propose that CMA could be an attractive therapeutic target against cardiovascular diseases

Short-term cooling increases serum angiopoietin-like 4 levels in healthy lean men

Background: Cold exposure enhances sympathetic outflow to peripheral tissues, thereby stimulating intracellular lipolysis in white adipose tissue and increasing the lipoprotein lipase-dependent uptake and combustion of triglyceride-derived fatty acids (FAs) by brown adipose tissue. Angiopoietin-like 4 (ANGPTL4) inhibits lipoprotein lipase and can be regulated by cold exposure, at least in mice. Objective: In the present study, we examined the effect of short-term mild cooling on serum ANGPTL4 levels in healthy lean men of White Caucasian and South Asian descent. Methods: Healthy, lean White Caucasian (n = 12) and South Asian (n = 12) men were exposed to an individualized cooling protocol for 2 hours. Serum ANGPTL4 levels were measured before and after cooling, and its relation with previously measured parameters (ie, free fatty acid [FFA] levels, body fat percentage, and resting energy expenditure) was determined. Results: Short-term cooling increased ANGPTL4 levels (+17%, P < .001). Thermoneutral ANGPTL4 levels positively correlated with FFA levels (R 2 = 0.250, P < .05) and body fat percentage (R 2 = 0.338, P < .05). Furthermore, ANGPTL4 negatively correlated with resting energy expenditure (R 2 = 0.235, P < .05). The relative increase in ANGPTL4 levels was higher in White Caucasians compared with South Asians (25 ± 4 vs 9 ± 4%, P < .05). Conclusion: Short-term cooling increases ANGPTL4 levels in healthy lean men. We anticipate that FFA liberated from white adipose tissue during cooling increases ANGPTL4 to limit uptake of triglyceride-derived FA by this tissue

The effects of selective hematopoietic expression of human IL-37 on systemic inflammation and atherosclerosis in LDLr-deficient mice

The human cytokine interleukin (IL)-37 has potent anti-inflammatory capacities, and hematopoietic cell-specific transgenic overexpression of IL-37 in mice protects against septic shock and colitis. In the present study we investigated the effect of hematopoietic expression of IL-37 on atherosclerosis development under low-grade inflammatory conditions. Low-density lipoprotein receptor (LDLr)-deficient mice were lethally irradiated and transplanted with bone marrow from IL-37-transgenic or control wild-type mice and fed a Western-type diet (WTD; 1% cholesterol) for eight weeks. Metabolic and inflammatory parameters were monitored and atherosclerosis was assessed in the aortic valve area. Hematopoietic IL-37 expression did not influence body weight, food intake and plasma cholesterol levels during the study. Plasma soluble E-selectin levels were increased with WTD-feeding as compared to chow-feeding, but were not influenced by IL-37 expression. IL-37 expression reduced the inflammatory state as indicated by reduced white blood cell counts and by reduced basal and lipopolysaccharide-induced cytokine response by peritoneal macrophages ex vivo. IL-37 expression did not influence the atherosclerotic lesion area. Lesion composition was marginally affected. Smooth muscle cell content was decreased, but macrophage and collagen content were not different. We conclude that under low-grade inflammatory conditions, hematopoietic IL-37 expression reduces the inflammatory state, but does not influence atherosclerosis development in hyperlipidemic LDLr-deficient mice.</p

Memory, Conflict and New Media: Web Wars in Post-Socialist States

This book examines the online memory wars in post-Soviet states - where political conflicts take the shape of heated debates about the recent past, and especially World War II and Soviet socialism. To this day, former socialist states face the challenge of constructing national identities, producing national memories, and relating to the Soviet legacy. Their pasts are principally intertwined: changing readings of history in one country generate fierce reactions in others. In this transnational memory war, digital media form a pivotal discursive space - one that provides speakers with radically new commemorative tools. Uniting contributions by leading scholars in the field, Memory, Conflict and New Media is the first book-length publication to analyse how new media serve as a site of political and national identity building in post-socialist states. The book also examines how the construction of online identity is irreversibly affected by thinking about the past in this geopolitical domain. By highlighting post-socialist memory’s digital mediations and digital memory’s transcultural scope, the volume succeeds in a twofold aim: to deepen and refine both (post-socialist) memory theory and digital-memory studies. This book will be of much interest to students of media studies, post-Soviet studies, Eastern European Politics, memory studies and International Relations in general

Akkermansia muciniphila Exerts Lipid-Lowering and Immunomodulatory Effects without Affecting Neointima Formation in Hyperlipidemic APOE*3-Leiden.CETP Mice

Scope: Akkermansia muciniphila (A. muciniphila) is an intestinal commensal with anti-inflammatory properties both in the intestine and other organs. The aim is to investigate the effects of oral administration of A. muciniphila on lipid metabolism, immunity, and cuff-induced neointima formation in hyperlipidemic APOE*3-Leiden (E3L).CETP mice. Methods and results: Hyperlipidemic male E3L.CETP mice are daily treated with 2 × 108 CFU A. muciniphila by oral gavage for 4 weeks and the effects are determined on plasma lipid levels, immune parameters, and cuff-induced neointima formation and composition. A. muciniphila administration lowers body weight and plasma total cholesterol and triglycerides levels. A. muciniphila influences the immune cell composition in mesenteric lymph nodes, as evident from an increased total B cell population, while reducing the total T cell and neutrophil populations. Importantly, A. muciniphila reduces the expression of the activation markers MHCII on dendritic cells and CD86 on B cells. A. muciniphila also increases whole blood ex vivo lipopolysaccharide-stimulated IL-10 release. Finally, although treatment with A. muciniphila improves lipid metabolism and immunity, it does not affect neointima formation or composition. Conclusions: Four weeks of treatment with A. muciniphila exerts lipid-lowering and immunomodulatory effects, which are insufficient to inhibit neointima formation in hyperlipidemic E3L.CETP mice.</p

Akkermansia muciniphila Exerts Lipid-Lowering and Immunomodulatory Effects without Affecting Neointima Formation in Hyperlipidemic APOE*3-Leiden.CETP Mice

Scope: Akkermansia muciniphila (A. muciniphila) is an intestinal commensal with anti-inflammatory properties both in the intestine and other organs. The aim is to investigate the effects of oral administration of A. muciniphila on lipid metabolism, immunity, and cuff-induced neointima formation in hyperlipidemic APOE*3-Leiden (E3L).CETP mice. Methods and results: Hyperlipidemic male E3L.CETP mice are daily treated with 2 × 108 CFU A. muciniphila by oral gavage for 4 weeks and the effects are determined on plasma lipid levels, immune parameters, and cuff-induced neointima formation and composition. A. muciniphila administration lowers body weight and plasma total cholesterol and triglycerides levels. A. muciniphila influences the immune cell composition in mesenteric lymph nodes, as evident from an increased total B cell population, while reducing the total T cell and neutrophil populations. Importantly, A. muciniphila reduces the expression of the activation markers MHCII on dendritic cells and CD86 on B cells. A. muciniphila also increases whole blood ex vivo lipopolysaccharide-stimulated IL-10 release. Finally, although treatment with A. muciniphila improves lipid metabolism and immunity, it does not affect neointima formation or composition. Conclusions: Four weeks of treatment with A. muciniphila exerts lipid-lowering and immunomodulatory effects, which are insufficient to inhibit neointima formation in hyperlipidemic E3L.CETP mice.</p

Disruption of circadian rhythm by alternating light-dark cycles aggravates atherosclerosis development in APOE*3-Leiden.CETP mice

Disruption of circadian rhythm by means of shift work has been associated with cardiovascular disease in humans. However, causality and underlying mechanisms have not yet been established. In this study, we exposed hyperlipidemic APOE*3-Leiden.CETP mice to either regular light-dark cycles, weekly 6 hours phase advances or delays, or weekly alternating light-dark cycles (12 hours shifts), as a well-established model for shift work. We found that mice exposed to 15 weeks of alternating light-dark cycles displayed a striking increase in atherosclerosis, with an approximately twofold increase in lesion size and severity, while mice exposed to phase advances and delays showed a milder circadian disruption and no significant effect on atherosclerosis development. We observed a higher lesion macrophage content in mice exposed to alternating light-dark cycles without obvious changes in plasma lipids, suggesting involvement of the immune system. Moreover, while no changes in the number or activation status of circulating monocytes and other immune cells were observed, we identified increased markers for inflammation, oxidative stress, and chemoattraction in the vessel wall. Altogether, this is the first study to show that circadian disruption by shifting light-dark cycles directly aggravates atherosclerosis development