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Our results demonstrate that acute exposure to tobacco smoking as well as electronic cigarettes influences vascular and respiratory function. Where tobacco smoking significantly increased microparticle formation, indicative of possible endothelial injury, electronic cigarettes use induced vasoreactivity and decreased peak expiratory flow. These findings suggest that both electronic cigarettes and tobacco smoking negatively impact vascular function.
Chaperone-mediated autophagy (CMA) is a major pathway of lysosomal proteolysis recognized as a key player of the control of numerous cellular functions, and whose defects have been associated with several human pathologies. To date, this cellular function is presumed to be restricted to mammals and birds, due to the absence of an identifiable lysosome-associated membrane protein 2A (LAMP2A), a limiting and essential protein for CMA, in nontetrapod species. However, the recent identification of expressed sequences displaying high homology with mammalian LAMP2A in several fish species challenges that view and suggests that CMA likely appeared earlier during evolution than initially thought. In the present study, we provide a comprehensive picture of the evolutionary history of the LAMP2 gene in vertebrates and demonstrate that LAMP2 indeed appeared at the root of the vertebrate lineage. Using a fibroblast cell line from medaka fish (Oryzias latipes), we further show that the splice variant lamp2a controls, upon long-term starvation, the lysosomal accumulation of a fluorescent reporter commonly used to track CMA in mammalian cells. Finally, to address the physiological role of Lamp2a in fish, we generated knockout medaka for that specific splice variant, and found that these deficient fish exhibit severe alterations in carbohydrate and fat metabolisms, in consistency with existing data in mice deficient for CMA in liver. Altogether, our data provide the first evidence for a CMA-like pathway in fish and bring new perspectives on the use of complementary genetic models, such as zebrafish or medaka, for studying CMA in an evolutionary perspective.
Nowadays, aquaculture provides more than 50% of fish consumed worldwide but faces new issues that challenge its sustainability. One of them relies on the replacement of fish meal (FM) in aquaculture feeds by other protein sources without deeply affecting the whole organism’s homeostasis. Multiple strategies have already been tested using in vivo approaches, but they hardly managed to cope with the multifactorial problems related to the complexities of fish biology together with new feed formulations. In this context, rainbow trout (RT) is particularly concerned by these problems, since, as a carnivorous fish, dietary proteins provide the amino acids required to supply most of its energetic metabolism. Surprisingly, we noticed that in vitro approaches considering RT cell lines as models to study RT amino acid metabolism were never previously used. Therefore, we decided to investigate if, and how, three major pathways described, in other species, to be regulated by amino acid and to control cellular homeostasis were functional in a RT cell line called RTH-149—namely, the mechanistic Target Of Rapamycin (mTOR), autophagy and the general control nonderepressible 2 (GCN2) pathways. Our results not only demonstrated that these three pathways were functional in RTH-149 cells, but they also highlighted some RT specificities with respect to the time response, amino acid dependencies and the activation levels of their downstream targets. Altogether, this article demonstrated, for the first time, that RT cell lines could represent an interesting alternative of in vivo experimentations for the study of fish nutrition-related questions.
Dysregulation of microRNAs (miRNAs) can contribute to the etiology of diseases, including pulmonary arterial hypertension (PAH). Here we investigated a potential role for the miR-214 stem loop miRNA and the closely linked miR-199a miRNAs in PAH. All 4 miRNAs were upregulated in the lung and right ventricle (RV) in mice and rats exposed to the Sugen (SU) 5416 hypoxia model of PAH. Further, expression of the miRNAs was increased in pulmonary artery smooth muscle cells exposed to transforming growth factor β1 but not BMP4. We then examined miR-214 −/− mice exposed to the SU 5416 hypoxia model of PAH or normoxic conditions and littermate controls. There were no changes in RV systolic pressure or remodeling observed between the miR-214 −/− and wild-type hypoxic groups. However, we observed a significant increase in RV hypertrophy (RVH) in hypoxic miR-214 −/− male mice compared with controls. Further, we identified that the validated miR-214 target phosphatase and tensin homolog was upregulated in miR-214 −/− mice. Thus, miR-214 stem loop loss leads to elevated RVH and may contribute to the heart failure associated with PAH. Pulmonary arterial hypertension (PAH) is a disease characterized by narrowing of the small pulmonary arteries, leading to vascular remodeling, an elevation in pulmonary artery pressure, right ventricular hypertrophy (RVH), and heart failure. 1 Current therapies for PAH aim to reverse the endothelial dysfunction and vasoconstriction observed. 2 However, despite these therapies, PAH mortality rates remain high, and the 3-year survival of patients is only 54.9%. 3 Changes in the pulmonary vasculature are the primary cause of PAH; however, right ventricle (RV) function is a major determinant of the severity of symptoms and prognosis of pulmonary hypertension. Many therapies in development for PAH are focused on targeting the RV since heart failure is the ultimate cause of mortality in PAH. 4 PAH is predominant in females, with female ∶ male ratios of 1.4-4.1 ∶ 1. 5 Sexual dimorphism has also been observed in RV failure. Female PAH patients exhibit improved RV ejection fraction and survival compared with men. 6 This could be due at least in part to the protective effect of estrogen on RV function. 7,8 MicroRNAs (miRNAs) are involved in multiple cellular responses during normal development and disease; they act as posttranscriptional regulators to fine-tune protein synthesis. Evidence has emerged for a key role for miRNA in regulation of the cellular processes involved in PAH. We previously demonstrated that a range of miRNAs are dysregulated in rats exposed to models of PAH. 9 Later studies have shown that miR-21, the miR-143/145 cluster, miR-27a, the miR-17-92 cluster, miR-124, miR-150, miR-138, miR-190, miR-204, miR-206, miR-210, and miR-328 play a role in the development of PAH. 10 Multiple miRNAs could potentially be targeted in concert as therapeutics in PAH. 11 MicroRNA miR-214 is transcribed as a bicistronic primary transcript, which is processed to generate 4 separate mature miRNAs...
Vascular smooth muscle cell (VSMC) dedifferentiation is a common feature of vascular disorders leading to pro-migratory and proliferative phenotypes, a process induced through growth factor and cytokine signaling cascades. Recently, many studies have demonstrated that small non-coding RNAs (miRNAs) can induce phenotypic effects on VSMCs in response to vessel injury. However, most studies have focused on the contribution of individual miRNAs. Our study aimed to conduct a detailed and unbiased analysis of both guide and passenger miRNA expression in vascular cells in vitro and disease models in vivo. We analyzed 100 miRNA stem loops by TaqMan Low Density Array (TLDA) from primary VSMCs in vitro. Intriguingly, we found that a larger proportion of the passenger strands was significantly dysregulated compared to the guide strands after exposure to pathological stimuli, such as platelet-derived growth factor (PDGF) and IL-1α. Similar findings were observed in response to injury in porcine vein grafts and stent models in vivo. In these studies, we reveal that the miRNA passenger strands are predominantly dysregulated in response to vascular injury.
Replacing fishmeal with alternative protein sources and improving new ingredients diets with feed additives are major objectives in aquaculture. The aim of this study was to evaluate benefits for rainbow trout (Oncorhynchus mykiss) of supplementing a fishmeal-free diet, composed of processed animal proteins, with yeast extract. Juvenile rainbow trout (initial weight 37 +/- 2 g) were fed either with a control diet (19% fishmeal) or with a diet based on terrestrial animal by-products (17%) supplemented or not with 3% of yeast extract. Effects of the diets were evaluated in a 4-week digestibility trial and a 12-week growth experiment. Fish health was investigated by measuring plasma immune markers and performing histological study of the gut. Underlying molecular responses were investigated using unbiased transcriptomic analysis of the liver and distal intestine. Results indicated that supplementing with 3% yeast extract did not influence nutrient digestibility substantially. Nevertheless, fish fed the supplemented fishmeal-free diet grew more than those fed the non-supplemented processed animal protein diet. Plasma and structural parameters indicated no exacerbated immune response or signs of intestinal inflammation in fish fed the fishmeal-free diets. However, plasma total immunoglobulin M levels and intestinal villi were significantly higher in fish fed the diet supplemented with yeast extract. The transcriptomic analysis revealed that the diets influenced immune, inflammatory, pathogen fighting and coagulation gene-related expressions. These results suggest that the dietary inclusion of yeast can enhance a fishmeal-free diet by improving rainbow trout performances and potentially their robustness.
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