An Evaluation of the Clinical Evidence on the Role of Inflammation and Oxidative Stress in Smoking-Mediated Cardiovascular Disease

The number of fatalities due to cardiovascular disease (CVD) continues to be far ahead of loss of human life caused by any other type of disease worldwide. According to the WHO, the annual global tobacco death toll is already 8.4 million and will reach 10 million by the year 2025. However, in contrast to other modifiable primary risk factors for CVD such as obesity, primary prevention strategies for smokers unable to quit are not available to date. This Review, by adopting the principles of evidence-based medicine, summarizes the most recent clinical studies on CVD in smokers, and concludes by suggesting a novel primary prevention strategy for CVD in smokers unable to quit. Evidence gathered from mechanistic studies involving basic research as well as large population-based approaches point to oxidative stress as the major insult imposed by cigarette smoke (CS), and a state of systemic inflammation, as signified by increased hs (high sensitivity) CRP levels in smokers, as the decisive pro-atherogenic response of the body to the initial insult. Since we identified oxidative stress induced by heavy metals as a significant pro-atherogenic activity of CS, strategies aimed at detoxifying heavy metals and combating inflammation appear as plausible approaches to counteract the accelerated onset of CVD in smokers. For this purpose, we discuss metal chelating agents and statins as promising novel primary prevention strategies in smokers unable to quit

Dietary Silicon Deficiency Does Not Exacerbate Diet-Induced Fatty Lesions in Female ApoE Knockout Mice.

BACKGROUND: Dietary silicon has been positively linked with vascular health and protection against atherosclerotic plaque formation, but the mechanism of action is unclear. OBJECTIVES: We investigated the effect of dietary silicon on 1) serum and aorta silicon concentrations, 2) the development of aortic lesions and serum lipid concentrations, and 3) the structural and biomechanic properties of the aorta. METHODS: Two studies, of the same design, were conducted to address the above objectives. Female mice, lacking the apolipoprotein E (apoE) gene, and therefore susceptible to atherosclerosis, were separated into 3 groups of 10-15 mice, each exposed to a high-fat diet (21% wt milk fat and 1.5% wt cholesterol) but with differing concentrations of dietary silicon, namely: silicon-deprived (-Si; <3-μg silicon/g feed), silicon-replete in feed (+Si-feed; 100-μg silicon/g feed), and silicon-replete in drinking water (+Si-water; 115-μg silicon/mL) for 15-19 wk. Silicon supplementation was in the form of sodium metasilicate (feed) or monomethylsilanetriol (drinking water). RESULTS: The serum silicon concentration in the -Si group was significantly lower than in the +Si-feed (by up to 78%; P < 0.003) and the +Si-water (by up to 84%; P < 0.006) groups. The aorta silicon concentration was also lower in the -Si group than in the +Si-feed group (by 65%; P = 0.025), but not compared with the +Si-water group. There were no differences in serum and aorta silicon concentrations between the silicon-replete groups. Body weights, tissue wet weights at necropsy, and structural, biomechanic, and morphologic properties of the aorta were not affected by dietary silicon; nor were the development of fatty lesions and serum lipid concentrations. CONCLUSIONS: These findings suggest that dietary silicon has no effect on atherosclerosis development and vascular health in the apoE mouse model of diet-induced atherosclerosis, contrary to the reported findings in the cholesterol-fed rabbit model

To Be Or Not to Be: the "Smoker's Paradox" - An in-Vitro Study

Background/Aims: Clinical studies have reported a better outcome of smokers after myocardial infarction compared to non-smokers. The data are controversial, as some clinical studies did not observe this effect. The cell biological processes involved, which might account for a 'Smoker's Paradox', have not been investigated yet. Therefore, the aim was to elucidate the effect of cigarette smoke on the viability of cardiomyocytes in the context of hypoxia and reperfusion. Methods: HL-1 cells were incubated with different concentrations of cigarette smoke extract (CSE) and subjected to hypoxia/reperfusion to further evaluate influence of CSE on viability of HL-1 cells using flow cytometry analyses, Western Blot and immunofluorescence staining. Results: Incubation with CSE led to a concentration-dependent reduction in HL-1 viability. Adding hypoxia as a stressor enhanced cell death. Caspase-independent apoptosis was the observed type of cell death partly induced by P53 and apoptosis-inducing-factor. Yet a significant increase in LDH release in cardiomyocytes incubated with 4%, 8% and 16% CSE suggests necrosis with rapid DNA depletion. Interestingly, after hypoxia a decreased LDH release under lower CSE concentrations was observed. Moreover, a concentration-dependent increase in proliferation and a trend for increased ATP availability under hypoxic conditions was shown. Conclusions: The trend for less LDH release in hypoxia after low-level CSE incubation might represent a switch from necrosis to apoptosis, which in combination with the increase in metabolic activity and ATP availability might account for the 'Smoker's Paradox'. These findings could partly explain inconsistent results of previous clinical studies as the data showed strong evidence for the crucial relevance of the amount of cigarettes smoked. We are in need of future studies distinguishing between different types of smokers to finally verify or falsify the 'Smoker's Paradox'

Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4

The chemokine receptor, CXC chemokine receptor 4 (CXCR4), is selective for CXC chemokine ligand 12 (CXCL12), is broadly expressed in blood and tissue cells, and is essential during embryogenesis and hematopoiesis. CXCL14 is a homeostatic chemokine with unknown receptor selectivity and preferential expression in peripheral tissues. Here, we demonstrate that CXCL14 synergized with CXCL12 in the induction of chemokine responses in primary human lymphoid cells and cell lines that express CXCR4. Combining subactive concentrations of CXCL12 with 100–300 nM CXCL14 resulted in chemotaxis responses that exceeded maximal responses that were obtained with CXCL12 alone. CXCL14 did not activate CXCR4-expressing cells (i.e., failed to trigger chemotaxis and Ca2+ mobilization, as well as signaling via ERK1/2 and the small GTPase Rac1); however, CXCL14 bound to CXCR4 with high affinity, induced redistribution of cell-surface CXCR4, and enhanced HIV-1 infection by >3-fold. We postulate that CXCL14 is a positive allosteric modulator of CXCR4 that enhances the potency of CXCR4 ligands. Our findings provide new insights that will inform the development of novel therapeutics that target CXCR4 in a range of diseases, including cancer, autoimmunity, and HIV.—Collins, P. J., McCully, M. L., Mart´ınez-Muñoz, L., Santiago, C.,Wheeldon, J., Caucheteux, S., Thelen, S., Cecchinato, V., Laufer, J.M., Purvanov, V.,Monneau, Y. R., Lortat-Jacob, H., Legler, D. F., Uguccioni, M., Thelen, M., Piguet, V., Mellado, M., Moser, B. Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4. FASEB J. 31, 000–000 (2017). www.fasebj.or

Dietary Silicon Deficiency Does Not Exacerbate Diet-Induced Fatty Lesions in Female ApoE Knockout Mice.

BACKGROUND: Dietary silicon has been positively linked with vascular health and protection against atherosclerotic plaque formation, but the mechanism of action is unclear. OBJECTIVES: We investigated the effect of dietary silicon on 1) serum and aorta silicon concentrations, 2) the development of aortic lesions and serum lipid concentrations, and 3) the structural and biomechanic properties of the aorta. METHODS: Two studies, of the same design, were conducted to address the above objectives. Female mice, lacking the apolipoprotein E (apoE) gene, and therefore susceptible to atherosclerosis, were separated into 3 groups of 10-15 mice, each exposed to a high-fat diet (21% wt milk fat and 1.5% wt cholesterol) but with differing concentrations of dietary silicon, namely: silicon-deprived (-Si; <3-μg silicon/g feed), silicon-replete in feed (+Si-feed; 100-μg silicon/g feed), and silicon-replete in drinking water (+Si-water; 115-μg silicon/mL) for 15-19 wk. Silicon supplementation was in the form of sodium metasilicate (feed) or monomethylsilanetriol (drinking water). RESULTS: The serum silicon concentration in the -Si group was significantly lower than in the +Si-feed (by up to 78%; P < 0.003) and the +Si-water (by up to 84%; P < 0.006) groups. The aorta silicon concentration was also lower in the -Si group than in the +Si-feed group (by 65%; P = 0.025), but not compared with the +Si-water group. There were no differences in serum and aorta silicon concentrations between the silicon-replete groups. Body weights, tissue wet weights at necropsy, and structural, biomechanic, and morphologic properties of the aorta were not affected by dietary silicon; nor were the development of fatty lesions and serum lipid concentrations. CONCLUSIONS: These findings suggest that dietary silicon has no effect on atherosclerosis development and vascular health in the apoE mouse model of diet-induced atherosclerosis, contrary to the reported findings in the cholesterol-fed rabbit model

Accumulation of α-synuclein mediates podocyte injury in Fabry nephropathy

Current therapies for Fabry disease are based on reversing intracellular accumulation of globotriaosylceramide (Gb3) by enzyme replacement therapy (ERT) or chaperone-mediated stabilization of the defective enzyme, thereby alleviating lysosomal dysfunction. However, their effect in the reversal of end-organ damage, like kidney injury and chronic kidney disease, remains unclear. In this study, ultrastructural analysis of serial human kidney biopsies showed that long-term use of ERT reduced Gb3 accumulation in podocytes but did not reverse podocyte injury. Then, a CRISPR/Cas9–mediated α-galactosidase knockout podocyte cell line confirmed ERT-mediated reversal of Gb3 accumulation without resolution of lysosomal dysfunction. Transcriptome-based connectivity mapping and SILAC-based quantitative proteomics identified α-synuclein (SNCA) accumulation as a key event mediating podocyte injury. Genetic and pharmacological inhibition of SNCA improved lysosomal structure and function in Fabry podocytes, exceeding the benefits of ERT. Together, this work reconceptualizes Fabry-associated cell injury beyond Gb3 accumulation, and introduces SNCA modulation as a potential intervention, especially for patients with Fabry nephropathy.publishedVersio