Nutriepigenetics and cardiovascular disease

Purpose of review: We present a current perspective of epigenetic alterations that can lead to cardiovascular disease (CVD) and the potential of dietary factors to counteract their actions. In addition, we discuss the challenges and opportunities of dietary treatments as epigenetic modifiers for disease prevention and therapy. Recent findings: Recent epigenome-wide association studies along with candidate gene approaches and functional studies in cell culture and animal models have delineated mechanisms through which nutrients, food compounds and dietary patterns may affect the epigenome. Several risk factors for CVD, including adiposity, inflammation and oxidative stress, have been associated with changes in histone acetylation, lower global DNA methylation levels and shorter telomere length. A surplus of macronutrients such as in a high-fat diet or deficiencies of specific nutrients such as folate and other B-vitamins can affect the activity of DNA methyltransferases and histone-modifying enzymes, affecting foetal growth, glucose/lipid metabolism, oxidative stress, inflammation and atherosclerosis. Bioactive compounds such as polyphenols (resveratrol, curcumin) or epigallocatechin may activate deacetylases Sirtuins (SIRTs), histone deacetylases or acetyltransferases and in turn the response of inflammatory mediators. Adherence to cardioprotective dietary patterns, such as the Mediterranean diet (MedDiet), has been associated with altered methylation and expression of genes related to inflammation and immuno-competence. Summary: The mechanisms through which nutrients and dietary patterns may alter the cardiovascular epigenome remain elusive. The research challenge is to determine which of these nutriepigenetic effects are reversible, so that novel findings translate into effective dietary interventions to prevent CVD or its progression

DNA Checkpoint and Repair Factors Are Nuclear Sensors for Intracellular Organelle Stresses-Inflammations and Cancers Can Have High Genomic Risks.

Under inflammatory conditions, inflammatory cells release reactive oxygen species (ROS) and reactive nitrogen species (RNS) which cause DNA damage. If not appropriately repaired, DNA damage leads to gene mutations and genomic instability. DNA damage checkpoint factors (DDCF) and DNA damage repair factors (DDRF) play a vital role in maintaining genomic integrity. However, how DDCFs and DDRFs are modulated under physiological and pathological conditions are not fully known. We took an experimental database analysis to determine the expression of 26 DNA D

Fatty Acid Oxidation Promotes Cardiomyocyte Proliferation Rate but Does Not Change Cardiomyocyte Number in Infant Mice

Cardiomyocyte proliferation accounts for the increase of cardiac muscle during fetal mammalian heart development. Shortly after birth, cardiomyocyte transits from hyperplasia to hypertrophic growth. Here, we have investigated the role of fatty acid β-oxidation in cardiomyocyte proliferation and hypertrophic growth during early postnatal life in mice. A transient wave of increased cell cycle activity of cardiomyocyte was observed between postnatal day 3 and 5, that proceeded as cardiomyocyte hypertrophic growth and maturation. Assessment of cardiomyocyte metabolism in neonatal mouse heart revealed a myocardial metabolic shift from glycolysis to fatty acid β-oxidation that coincided with the burst of cardiomyocyte cell cycle reactivation and hypertrophic growth. Inhibition of fatty acid β-oxidation metabolism in infant mouse heart delayed cardiomyocyte cell cycle exit, hypertrophic growth and maturation. By contrast, pharmacologic and genetic activation of PPARα, a major regulator of cardiac fatty acid metabolism, induced fatty acid β-oxidation and initially promoted cardiomyocyte proliferation rate in infant mice. As the cell cycle proceeded, activation of PPARα-mediated fatty acid β-oxidation promoted cardiomyocytes hypertrophic growth and maturation, which led to cell cycle exit. As a consequence, activation of PPARα-mediated fatty acid β-oxidation did not alter the total number of cardiomyocytes in infant mice. These findings indicate a unique role of fatty acid β-oxidation in regulating cardiomyocyte proliferation and hypertrophic growth in infant mice

Inhibition of NADPH oxidase 2 (NOX2) prevents sepsis-induced cardiomyopathy by improving calcium handling and mitochondrial function

Cardiomyopathy frequently complicates sepsis and is associated with increased mortality. Increased cardiac oxidative stress and mitochondrial dysfunction have been observed during sepsis, but the mechanisms responsible for these abnormalities have not been determined. We hypothesized that NADPH oxidase 2 (NOX2) activation could be responsible for sepsis-induced oxidative stress and cardiomyopathy. Treatment of isolated adult mouse cardiomyocytes with low concentrations of the endotoxin lipopolysaccharide (LPS) increased total cellular reactive oxygen species (ROS) and mitochondrial superoxide. Elevated mitochondrial superoxide was accompanied by depolarization of the mitochondrial inner membrane potential, an indication of mitochondrial dysfunction, and mitochondrial calcium overload. NOX2 inhibition decreased LPS-induced superoxide and prevented mitochondrial dysfunction. Further, cardiomyocytes from mice with genetic ablation of NOX2 did not have LPS-induced superoxide or mitochondrial dysfunction. LPS decreased contractility and calcium transient amplitude in isolated cardiomyocytes, and these abnormalities were prevented by inhibition of NOX2. LPS decreased systolic function in mice, measured by echocardiography. NOX2 inhibition was cardioprotective in 2 mouse models of sepsis, preserving systolic function after LPS injection or cecal ligation and puncture (CLP). These data show that inhibition of NOX2 decreases oxidative stress, preserves intracellular calcium handling and mitochondrial function, and alleviates sepsis-induced systolic dysfunction in vivo. Thus, NOX2 is a potential target for pharmacotherapy of sepsis-induced cardiomyopathy

Gene regulation and functions of apolipoprotein E

1st chapter: Role of the transcriptional factor c-Jun in the regulation of genes that affect lipid homeostasis in vivo. c-Jun (cellular Jun) is a transcription factor activated by phosphorylation by the stress activated protein kinase/c-Jun-N-terminal-kinase pathway in response to extracellular signals and cytokines. We show that adenovirus mediated gene transfer of dn-c-Jun (dominant negative form of c-Jun) in C57BL/6 mice increased greatly apoE (apolipoprotein E) hepatic mRNA and plasma levels, increased plasma cholesterol, triglyceride and VLDL (very low density lipoprotein) levels and resulted in the accumulation of discoidal HDL (high density lipoprotein). A similar but more severe phenotype was generated by overexpression of the mouse apoE in C57BL/6 mice, suggesting that dyslipidemia induced by dn-c-Jun was the result of apoE overexpression. Unexpectedly, infection of apoE-/- mice with adenovirus expressing dn-c-Jun reduced by 70% plasma cholesterol, suggesting that dn-c-Jun affected other genes that control plasma cholesterol levels. To identify these genes we performed whole genome expression analysis (34,000 genes) of isolated livers from two groups of five apoE-/- mice, infected with adenoviruses expressing either the dn-c-Jun or the green fluorescence protein. Bioinformatical analysis and Northern blotting validation revealed that dn-c-Jun increased 40-fold the apoE mRNA and reduced by 70% the Scd-1 (stearoyl-CoA-desaturase 1) mRNA. The involvement of Scd-1 in lowering plasma cholesterol was confirmed by restoration of high cholesterol levels of apoE-/-mice following coinfection with adenoviruses expressing dn-c-Jun and Scd-1. In conclusion, dn-c-Jun appears to trigger two opposing events in mice that affect plasma cholesterol and triglyceride levels: One results in apoE overexpression and triggers dyslipidemia and the other results in inhibition of Scd-1 and offsets dyslipidemia. The ability of the dn-c-Jun to upregulate the apoE gene expression is unique for the dn-c-Jun molecule since the wild type c-Jun as well as a constitutively active and an inactive mutant of the c-Jun did not affect the hepatic apoE mRNA levels. […]1η Θεματική Ενότητα – Ρόλος του μεταγραφικού παράγοντα c-Jun στη ρύθμιση της έκφρασης γονιδίων που επηρεάζουν την ομοιόσταση των λιπιδίων in vivo. Ο c-Jun είναι ένας μεταγραφικός παράγοντας που ενεργοποιείται με φωσφορυλίωση από την κινάση JNK/SAPK μετά την επίδραση εξωκυτταρικών σημάτων και κυτοκινών. Η μελέτη αυτή έδειξε ότι η χορήγηση ενός ανασυνδυασμένου αδενοϊού, που εκφράζει μια επικρατούσα ανασταλτική μορφή του c-Jun (dn-c-Jun), σε ποντίκια C57BL/6 αύξησε σημαντικά τα επίπεδα ηπατικού mRNA της αποΕ και τα επίπεδα της αποΕ στο πλάσμα. Η αύξηση αυτή συνοδεύτηκε από αύξηση των επιπέδων χοληστερόλης, των τριγλυκεριδίων και των VLDL του πλάσματος και προκάλεσε συσσώρευση δισκοειδών σωματιδίων HDL. Παρόμοιος αλλά πολύ εντονότερος φαινότυπος προκλήθηκε από την υπερέκφραση της αποΕ του ποντικιού σε ποντίκια C57BL/6, οδηγώντας στο συμπέρασμα ότι η δυσλιπιδαιμία που προκλήθηκε από το dn-c-Jun οφείλονταν στην αύξηση της έκφρασης του γονιδίου της αποΕ. Χορήγηση του αδενοϊού που εκφράζει τον dn-c-Jun σε ποντίκια απόΕ-/- προκάλεσε απροσδόκητη μείωση των επιπέδων των λιπιδίων του πλάσματος οδηγώντας στο συμπέρασμα ότι ο dn-c-Jun επηρεάζει και άλλα γονίδια, εκτός της αποΕ, τα οποία ελέγχουν τα επίπεδα της χοληστερόλης του πλάσματος. Για τον προσδιορισμό αυτών των γονιδίων έγινε ανάλυση του ηπατικού mRNA των ποντικιών αποΕ-/- που μολύνθηκαν με αδενοϊό που εκφράζει τον dn-c-Jun με μικροσυστοιχίες για τον σύνολο των γονιδίων του ποντικιού. Βιοπληροφορική ανάλυση και ανάλυση κατά Northern επιβεβαίωσαν την αύξηση της έκφρασης του γονιδίου της αποΕ και έδειξαν ότι συνέβη μείωση της έκφρασης του γονιδίου της Scd-1 (Stearoyl-CoA-desaturase 1). Η συμβολή της μείωσης της έκφρασης του γονιδίου της Scd-1 στη μείωση της χοληστερόλης του πλάσματος επιβεβαιώθηκε με αποκατάσταση των υψηλών επιπέδων χοληστερόλης του πλάσματος μετά από ταυτόχρονη χορήγηση αδενοϊών που εκφράζουν τον dn-c-Jun και την Scd-1. Συμπερασματικά, η μελέτη αυτή έδειξε ότι το dn-c-Jun επάγει δύο ανεξάρτητα γεγονότα τα οποία επηρεάζουν με αντίθετο τρόπο τα επίπεδα χοληστερόλης και τριγλυκεριδίων του πλάσματος των ποντικιών. Αφ’ ενός αυξάνει την αποΕ, η οποία προκαλεί δυσλιπιδαιμία, αφ’ ετέρου προκαλεί μείωση της Scd-1 που οδηγεί σε περιορισμό της δυσλιπιδαιμίας. Ο ρόλος του dn-c-Jun στην ομοιόσταση των λιπιδίων και των λιποπρωτεϊνών φαίνεται να είναι μοναδικός, αφού χορήγηση ανασυνδυασμένων αδενοϊών που εκφράζουν τον αγρίου τύπου c-Jun καθώς και μια συνεχώς εκφραζόμενη μορφή του c-Jun και μια ανενεργή μορφή του c-Jun δεν προκαλούν μεταβολές στα λιπίδια του πλάσματος των ποντικιών C57BL/6. Στη συνέχεια περιγράφονται αναλυτικά τα πειράματα κατασκευής ανασυνδυασμένων αδενοϊών και η χρήση τους για τη μελέτη in vivo του ρόλου των πρωτεϊνών που εκφράζουν στη ρύθμιση των γονιδίων που σχετίζονται με την ομοιόσταση των λιπιδίων. […

The Use of Blockchain Technology in e-Government Services

e-Government services have evolved significantly over the last decade, from a paper-based bureaucratic procedure to digital services. Electronically processed transactions require limited physical interaction with the public administration, and provide reduced response times, increased transparency, confidentiality and integrity. Blockchain technology enhances many of the above properties as it facilitates immutability and transparency for the recorded transactions and can help establish trust among participants. In this paper, we conduct a literature review on the use of blockchain technology in e-government applications to identify e-government services that can benefit from the use of blockchains, types of technologies that are chosen for the proposed solutions, and their corresponding maturity levels. The aim is to demonstrate blockchain’s potential and contribution to the field, provide useful insights to governments who are considering investing in this innovative technology, and facilitate researchers in their future activities in blockchain-enabled e-government services

The Use of Blockchain Technology in e-Government Services

e-Government services have evolved significantly over the last decade, from a paper-based bureaucratic procedure to digital services. Electronically processed transactions require limited physical interaction with the public administration, and provide reduced response times, increased transparency, confidentiality and integrity. Blockchain technology enhances many of the above properties as it facilitates immutability and transparency for the recorded transactions and can help establish trust among participants. In this paper, we conduct a literature review on the use of blockchain technology in e-government applications to identify e-government services that can benefit from the use of blockchains, types of technologies that are chosen for the proposed solutions, and their corresponding maturity levels. The aim is to demonstrate blockchain’s potential and contribution to the field, provide useful insights to governments who are considering investing in this innovative technology, and facilitate researchers in their future activities in blockchain-enabled e-government services

PPARs: Protectors or Opponents of Myocardial Function?

Over 5 million people in the United States suffer from the complications of heart failure (HF), which is a rapidly expanding health complication. Disorders that contribute to HF include ischemic cardiac disease, cardiomyopathies, and hypertension. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family. There are three PPAR isoforms: PPARα, PPARγ, and PPARδ. They can be activated by endogenous ligands, such as fatty acids, as well as by pharmacologic agents. Activators of PPARs are used for treating several metabolic complications, such as diabetes and hyperlipidemia that are directly or indirectly associated with HF. However, some of these drugs have adverse effects that compromise cardiac function. This review article aims to summarize the current basic and clinical research findings of the beneficial or detrimental effects of PPAR biology on myocardial function