Long-term dietary n3 fatty acid prevents aging-related cardiac diastolic and vascular dysfunction

Aims: The prevalence of left ventricular (LV) diastolic and vascular dysfunction increases with age, eventually leading to heart failure with preserved ejection fraction (HFpEF). A preventive strategy is an unmet medical need. We and others reported previously on the beneficial effects of omega-3 fatty acid alpha linolenic acid (ALA) on cardiovascular disorders in animal models and translational studies. We now investigate whether long-term dietary ALA could prevent LV diastolic dysfunction and vascular aging in a murine model. Methods and results: Wild-type C57BL/6 J mice were fed a chow or ALA diet for 12 months, starting at 6 months of age. Here, we show that aged (~18 months) mice recapitulate major hallmarks of HFpEF, including LV diastolic dysfunction with preserved ejection fraction, impaired vascular function, cardiac fibrosis, arterial stiffening and inflammation, as well as elevated B-type natriuretic peptide (BNP). Long-term ALA supplementation upregulated the mitochondrial tricarboxylic acid enzyme Idh2 and the antioxidant enzymes SOD1 and Gpx1. It also has been associated with reduced inflammation and ECM remodeling, accompanied by a significant downregulation of fibrosis biomarkers MMP-2 and TGF-β in both cardiac and vascular tissues obtained from aged mice. Our data exhibited the preventive effects of dietary ALA against LV diastolic dysfunction, impaired vasorelaxation, cardiac fibrosis, inflammation and arterial stiffening in aged mice. Conclusions: We provide evidence and a simplified mechanistic insight on how long-term ALA supplementation is a successful strategy to prevent the development of age-related diastolic and vascular dysfunction

Circulating GDF11 exacerbates myocardial injury in mice and associates with increased infarct size in humans

AIMS The heart rejuvenating effects of circulating growth differentiation factor 11 (GDF11), a transforming growth factor-β superfamily member that shares 90% homology with myostatin (MSTN), remains controversial. Here, we aimed to probe the role of GDF11 in acute myocardial infarction (MI), a frequent cause of heart failure and premature death during ageing. METHODS AND RESULTS In contrast to endogenous Mstn, myocardial Gdf11 declined during the course of ageing and was particularly reduced following ischaemia/reperfusion (I/R) injury, suggesting a therapeutic potential of GDF11 signalling in MI. Unexpectedly, boosting systemic Gdf11 by recombinant GDF11 delivery (0.1 mg/kg body weight over 30 days) prior to myocardial I/R augmented myocardial infarct size in C57BL/6 mice irrespective of their age, predominantly by accelerating pro-apoptotic signalling. While intrinsic cardioprotective signalling pathways remained unaffected by high circulating GDF11, targeted transcriptomics and immunomapping studies focusing on GDF11-associated downstream targets revealed attenuated Nkx2-5 expression confined to CD105-expressing cells, with pro-apoptotic activity, as assessed by caspase-3 levels, being particularly pronounced in adjacent cells, suggesting an indirect effect. By harnessing a highly specific and validated liquid chromatography-tandem mass spectrometry-based assay, we show that in prospectively recruited patients with MI circulating GDF11 but not MSTN levels incline with age. Moreover, GDF11 levels were particularly elevated in those at high risk for adverse outcomes following the acute event, with circulating GDF11 emerging as an independent predictor of myocardial infarct size, as estimated by standardized peak creatine kinase-MB levels. CONCLUSION Our data challenge the initially reported heart rejuvenating effects of circulating GDF11 and suggest that high levels of systemic GDF11 exacerbate myocardial injury in mice and humans alike. Persistently high GDF11 levels during ageing may contribute to the age-dependent loss of cardioprotective mechanisms and thus poor outcomes of elderly patients following acute MI

Endothelial SIRT6 deficiency promotes arterial thrombosis in mice

OBJECTIVE Arterial thrombosis may be initiated by endothelial inflammation or denudation, activation of blood-borne elements or the coagulation system. Tissue factor (TF), a central trigger of the coagulation cascade, is regulated by the pro-inflammatory NF-κB-dependent pathways. Sirtuin 6 (SIRT6) is a nuclear member of the sirtuin family of NAD$^{+}$-dependent deacetylases and is known to inhibit NF-κB signaling. Its constitutive deletion in mice shows early lethality with hypoglycemia and accelerated aging. Of note, the role of SIRT6 in arterial thrombosis remains unknown. Thus, we hypothesized that endothelial SIRT6 protects from arterial thrombosis by modulating inhibition of NF-κB-associated pathways. APPROACH AND RESULTS Using a laser-induced carotid thrombosis model, in vivo arterial occlusion occurred 45% faster in 12-week-old male endothelial-specific Sirt6$^{-/-}$ mice as compared to Sirt6$^{fl/fl}$ controls (n ≥ 9 per group; p = 0.0012). Levels of procoagulant TF were increased in animals lacking endothelial SIRT6 as compared to control littermates. Similarly, in cultured human aortic endothelial cells, SIRT6 knockdown increased TF mRNA, protein and activity. Moreover, SIRT6 knockdown increased mRNA levels of NF-κB-associated genes tumor necrosis factor alpha (TNF-α), poly [ADP-ribose] polymerase 1 (PARP-1), vascular cell adhesion molecule 1 (VCAM-1), and cyclooxygenase-2 (COX-2); at the protein level, COX-2, VCAM-1, TNF-α, and cleaved PARP-1 remained increased after Sirt6 knockdown. CONCLUSIONS Endothelium-specific Sirt6 deletion promotes arterial thrombosis in mice. In cultured human aortic endothelial cells, SIRT6 silencing enhances TF expression and activates pro-inflammatory pathways including TNF-α, cleaved PARP-1, VCAM-1 and COX-2. Hence, endogenous endothelial SIRT6 exerts a protective role in experimental arterial thrombosis

Investigation and visualization of the approaches mobilizing the concept of health of the environment

Precise terminology is essential for every field for developing problem-solving strategies. It also helps to establish effective legislation and management frameworks. The field of environmental sciences is not an exception. A fast and accurate reaction to environmental issues can lead to fruitful results and prevent catastrophes. In order to improve performance, various approaches are created and thoroughly studied which appear to be more efficient when used for specific situations and aims. Therefore, it is important to have a good understanding of synonymously appearing approaches. The thesis’s objective was to present and investigate the existing approaches addressing the concept of health of the environment. The study aims to achieve it via statistical analysis of scientific literature mentioning the terminology associated with the approaches. Graphs on the historical development of terms were created to demonstrate the general trends occurring in the field and fluctuations in the popularity of each term. An analysis of the disciplines using the terms was performed to reveal possible similarities and overlaps in approaches known by different names. Finally, a keyword analysis was performed in VOSviewer aiming to demonstrate the environment’s role in the approaches. The study confirmed an existing increase in the popularity of the terms preferred in the scientific literature. It also revealed great convergence between the approaches of ecological health and ecosystem health. The results also indicated that the majority of the approaches show more anthropocentric than biocentric qualities. The study partially achieved its objectives since for a proper study of some approaches available literature was insufficient

The adaptor protein c-Cbl-associated protein (CAP) limits pro-inflammatory cytokine expression by inhibiting the NF-κB pathway

C-Cbl-associated protein (CAP), also known as Sorbin and SH3 domain-containing protein 1 (Sorbs1) or ponsin, an adaptor protein of the insulin-signalling pathway, mediates anti-viral and anti-cytotoxic protection in acute viral heart disease. In the present study we describe a novel protective immuno-modulatory function of CAP in inflammation. Among the three members of the Sorbs family of adapter molecules, which include CAP (Sorbs1), ArgBP2 (Sorbs2), and Vinexin (Sorbs3), CAP consistently down-regulated the expression of pro-inflammatory cytokines in mouse fibroblasts, cardiomyocytes, and myeloid-derived leukocytes, after Toll-like receptor (TLR) stimulation. Upon the same TLR stimulation, ArgBP2 partially down-regulated pro-inflammatory cytokine production in mouse fibroblasts and cardiomyocytes, while Vinexin rather promoted their production. Mechanistically, CAP limited pro-inflammatory cytokine expression by suppressing the phosphorylation of Inhibitor of kappa B (IκB) kinase (Iκκ)-α and Iκκ-β and their downstream NF-κB-dependent signalling pathway. Molecular affinity between CAP and Iκκ-α/ Iκκ-β was necessary to block the NF-κB pathway. The CAP-dependent inhibitory mechanism - in vivo exclusively IL-6 inhibition - was confirmed after collecting blood from mice with systemic inflammation induced by lipopolysaccharide (LPS) and in the heart tissue collected from mice infected with the cardiotropic Coxsackievirus B3 (CVB3). Taken together, CAP down-regulates pro-inflammatory cytokines by interfering with the normal function of the NF-κB pathway. The promotion of CAP production could support the development of new strategies aiming to limit excessive and detrimental activation of the immune system

Individual whole-body concentration of (137)Cesium is associated with decreased blood counts in children in the Chernobyl-contaminated areas, Ukraine, 2008-2010.

The Narodichesky region, Zhitomir Oblast, Ukraine, is situated ∼80 km from the Chernobyl Nuclear Power Plant, which exploded in 1986 and polluted the environment. A previous study found that children living in villages with high activity of (137)Cesium (Cs) in the soil had decreased levels of hemoglobin, erythrocytes and thrombocytes. These findings motivated the present study that used a more comprehensive exposure assessment, including individual whole-body concentrations (WBC) of (137)Cs (Bq/kg). This cross-sectional sample examined between 2008-2010, included 590 children in the age 0-18 years. Children with higher individual log(WBC) activity in the body had significantly decreased hemoglobin, erythrocyte and thrombocyte counts. The effect of log(WBC) on decreased thrombocyte count was only seen in children older than 12 years. The average village activity of (137)Cs (kBq/m(2)) in soil was associated with decreased blood counts only indirectly, through (137)Cs in the body as an intermediate variable. Children in this study were born at least 4 years after the accident and thus exposed to low doses of ionizing radiation from (137)Cs. This cross-sectional study indicates that low levels may be associated with decreased blood counts, but we cannot exclude that these results are due to residual confounding factors.Journal of Exposure Science and Environmental Epidemiology advance online publication, 25 September 2013; doi:10.1038/jes.2013.60

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1): a crucial driver of atherosclerotic cardiovascular disease

Cardiovascular diseases (CVDs), specifically lipid-driven atherosclerotic CVDs, remain the number one cause of death worldwide. The lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1), a scavenger receptor that promotes endothelial dysfunction by inducing pro-atherogenic signalling and plaque formation via the endothelial uptake of oxidized LDL (oxLDL) and electronegative LDL, contributes to the initiation, progression, and destabilization of atheromatous plaques, eventually leading to the development of myocardial infarction and certain forms of stroke. In addition to its expression in endothelial cells, LOX-1 is expressed in macrophages, cardiomyocytes, fibroblasts, dendritic cells, lymphocytes, and neutrophils, further implicating this receptor in multiple aspects of atherosclerotic plaque formation. LOX-1 holds promise as a novel diagnostic and therapeutic target for certain CVDs; therefore, understanding the molecular structure and function of LOX-1 is of critical importance. In this review, we highlight the latest scientific findings related to LOX-1, its ligands, and their roles in the broad spectrum of CVDs. We describe recent findings from basic research, delineate their translational value, and discuss the potential of LOX-1 as a novel target for the prevention, diagnosis, and treatment of related CVDs