The genetics of cardiovascular disease

Recent advances in genotyping technology and insights into disease mechanisms have increased interest in the genetics of cardiovascular disease. Several candidate genes involved in cardiovascular diseases were identified from studies using animal models, and the translation of these findings to human disease is an exciting challenge. There is a trend towards large-scale genome-wide association studies that are subject to strict quality criteria with regard to both genotyping and phenotyping. Here, we review some of the strategies that have been developed to translate findings from experimental models to human disease and outline the need for optimizing global approaches to analyze such results. Findings from ongoing studies are interpreted in the context of disease pathways instead of the more traditional focus on single genetic variants

Investigating interactions between epicardial adipose tissue and cardiac myocytes: what can we learn from different approaches?

Heart disease is a major cause of morbidity and mortality throughout the world. Some cardiovascular conditions can be modulated by lifestyle factors such as increased exercise or a healthier diet, but many require surgical or pharmacological interventions for their management. More targeted and less invasive therapies would be beneficial. Recently it has become apparent that epicardial adipose tissue plays an important role in normal and pathological cardiac function, and it is now the focus of considerable research. Epicardial adipose tissue can be studied by imaging of various kinds, and these approaches have yielded much useful information. However at a molecular level it is more difficult to study as it is relatively scarce in animal models and, for practical and ethical reasons, not always available in sufficient quantities from patients. What is needed is a robust model system in which the interactions between epicardial adipocytes and cardiac myocytes can be studied, and physiologically relevant manipulations performed. There are drawbacks to conventional culture methods, not least the difficulty of culturing both cardiac myocytes and adipocytes, each of which has special requirements. We discuss the benefits of a three-dimensional co-culture model in which in vivo interactions can be replicated

Chromosome 1p13 genetic variants antagonize the risk of myocardial infarction associated with high ApoB serum levels

PMCID: PMC3480949This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Myristic acid: in vivo evaluation of connection with cardiovascular risk factors and in vitro proteomic investigations of its biochemical effects

Fatty acids (FAs) are fundamental constituents of cell structure, but they can also influence cellular functions and molecular mechanisms with different effects according to their chain length and degree of saturation. Different pathological conditions have been linked to FAs profile, including dyslipidemia and hypertriglyceridemia. However, data concerning the effects of FAs on lipid metabolism and cardiovascular disease are still scarce and controversial. Therefore, the aim of the first part of the present PhD thesis (Section 1) has been to investigate the presence of possible significant correlations between plasma FAs profile and lipid parameters (including levels of the major apolipoproteins) in a population of Coronary Artery Disease (CAD) patients and controls. The analysis, performed on plasma of 1,370 subjects, revealed that Myristic acid (C14:0) positively predicted both Triglycerides (TG) and Apolipoprotein C-III (ApoC-III) plasma levels, confirming the preliminary data obtained in my master\u2019s degree thesis on 57 CAD patients. ApoC-III being an important regulator of plasma TG levels, the influence of C14:0 on the expression of this protein has been investigated in a HepG2 cell model. Mass spectrometry results, together with Real Time PCR findings, suggest a slight but significant increase in ApoC-III protein and mRNA levels in C14:0 treated cells. Therefore, the in vitro investigations supported the positive connection observed in-vivo between C14:0, TG and ApoC-III plasma levels, suggesting a possible important role of this saturated FA in the onset of cardiovascular disease. The effects of FAs on liver metabolism have been studied during the last few years for the influence they have on lipid metabolism, the onset of nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease. However, proteomics investigations in this direction are still scarce and the influence of C14:0 on liver metabolism still needs to be elucidated. Therefore, in the second part of the present PhD thesis (Section 2) the effects of different concentrations of C14:0 on HepG2 cells proteome and secretome have been investigated by means of high\u2013resolution mass spectrometry. The results obtained highlighted the influence of this FA on proteins involved in lipid droplets formation, cytoskeleton organization, endoplasmic reticulum stress, exosome release and cell-cell stress communication. To highlight the proteome changes specifically related to C14:0, a comparative study of the proteomic modulations induced by C14:0, palmitic (C16:0) and oleic acid (C18:1) has been performed. Interestingly, the overlapping of modulated proteins induced by the three FAs treatments was limited to just one protein, highlighting their different mechanisms of action. 40 proteins were found to be deregulated specifically by C14:0. These results suggested a unique influence of this saturated FA on specific proteins involved in different biological processes, mainly protein homeostasis counteracting ER stress (e.g. ENTPD5, VAPB and SGTA) and lipid metabolism (e.g. ApoE). In conclusion, the present PhD thesis highlights for the first time a possible in-vivo fundamental role of C14:0 on lipid metabolism, particularly on ApoC-III and TG plasma levels and represents the first investigation shedding light on the in-vitro C14:0 effects on a human hepatocyte-derived cell line

Plasma lipoprotein subfraction concentrations are associated with lipid metabolism and age-related macular degeneration

10.1194/jlr.M073684Journal of Lipid Research5891785-179

Comparative genomic analyses identify common molecular pathways modulated upon exposure to low doses of arsenic and cadmium

<p>Abstract</p> <p>Background</p> <p>Exposure to the toxic metals arsenic and cadmium is associated with detrimental health effects including cancers of various organs. While arsenic and cadmium are well known to cause adverse health effects at high doses, the molecular impact resulting from exposure to environmentally relevant doses of these metals remains largely unexplored.</p> <p>Results</p> <p>In this study, we examined the effects of <it>in vitro </it>exposure to either arsenic or cadmium in human TK6 lymphoblastoid cells using genomics and systems level pathway mapping approaches. A total of 167 genes with differential expression were identified following exposure to either metal with surprisingly no overlap between the two. Real-time PCR was used to confirm target gene expression changes. The gene sets were overlaid onto protein-protein interaction maps to identify metal-induced transcriptional networks. Interestingly, both metal-induced networks were significantly enriched for proteins involved in common biological processes such as tumorigenesis, inflammation, and cell signaling. These findings were further supported by gene set enrichment analysis.</p> <p>Conclusions</p> <p>This study is the first to compare the transcriptional responses induced by low dose exposure to cadmium and arsenic in human lymphoblastoid cells. These results highlight that even at low levels of exposure both metals can dramatically influence the expression of important cellular pathways.</p

Acetylsalicylic acid, aging and coronary artery disease are associated with ABCA1 DNA methylation in men

BACKGROUND: Previous studies have suggested that DNA methylation contributes to coronary artery disease (CAD) risk variability. DNA hypermethylation at the ATP-binding cassette transporter A1 (ABCA1) gene, an important modulator of high-density lipoprotein cholesterol and reverse cholesterol transport, has been previously associated with plasma lipid levels, aging and CAD, but the association with CAD has yet to be replicated. RESULTS: ABCA1 DNA methylation levels were measured in leucocytes of 88 men using bis-pyrosequencing. We first showed that DNA methylation at the ABCA1 gene promoter locus is associated with aging and CAD occurrence in men (P < 0.05). The latter association is stronger among older men with CAD (≥61 years old; n = 19), who showed at least 4.7% higher ABCA1 DNA methylation levels as compared to younger men with CAD (<61 years old; n = 19) or men without CAD (n = 50; P < 0.001). Higher ABCA1 DNA methylation levels in older men were also associated with higher total cholesterol (r = 0.34, P = 0.03), low-density lipoprotein cholesterol (r = 0.32, P = 0.04) and triglyceride levels (r = 0.26, P = 0.09). Furthermore, we showed that acetylsalicylic acid therapy is associated with 3.6% lower ABCA1 DNA methylation levels (P = 0.006), independent of aging and CAD status of patients. CONCLUSIONS: This study provides new evidence that the ABCA1 epigenetic profile is associated with CAD and aging, and highlights that epigenetic modifications might be a significant molecular mechanism involved in the pathophysiological processes associated with CAD. Acetylsalicylic acid treatment for CAD prevention might involve epigenetic mechanisms