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Publications (18)

  • Costas Psarros · Regent Lee · Alexios Antonopoulos · [...] · Charalambos Antoniades
    Chapter · Feb 2016
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    [Show abstract] [Hide abstract] ABSTRACT: Rationale: Adiponectin has anti-inflammatory effects in experimental models but its role in the regulation of myocardial redox state in humans is unknown. Although adiponectin is released from epicardial adipose tissue (EpAT), it is unclear whether it exerts any paracrine effects on the human myocardium. Objective: To explore the cross-talk between EpAT-derived adiponectin and myocardial redox state in the human heart. Methods and results: EpAT and atrial myocardium were obtained from 306 patients undergoing CABG. Functional genetic polymorphisms that increase ADIPOQ expression (encoding adiponectin) led to reduced myocardial NADPH oxidase-derived O2.(-), whereas circulating adiponectin and ADIPOQ expression in EpAT were associated with elevated myocardial O2.(-). In human atrial tissue, we demonstrated that adiponectin suppresses myocardial NADPH oxidase activity, by preventing AMP kinase-mediated translocation of Rac1 and p47(phox) from the cytosol to the membranes. Induction of O2.(-) production in H9C2 cardiac myocytes led to the release of a transferable factor able to induce PPAR-γ mediated up-regulation of ADIPOQ expression in co-cultured EpAT. Using a NOX2 transgenic mouse and a pig model of rapid atrial pacing, we found that oxidation products (such as 4-hydroxynonenal) released from the heart trigger PPAR-γ mediated up-regulation of ADIPOQ in EpAT. Conclusions: We demonstrate for the first time in humans, that adiponectin directly decreases myocardial NADPH oxidase activity via endocrine or paracrine effects. Adiponectin expression in EpAT is controlled by paracrine effects of oxidation products released from the heart. These effects constitute a novel defence mechanism of the heart against myocardial oxidative stress.
    Full-text Article · Feb 2016 · Circulation Research
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    [Show abstract] [Hide abstract] ABSTRACT: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the industrialized world and in the future is expected to be the number one killer worldwide. The main cause underlying CVD is atherosclerosis. A key event in atherosclerosis initiation and progression is oxidative stress through the production of reactive oxygen species as well as endothelial dysfunction. Several pro- inflammatory and anti-inflammatory cytokines and proteins are involved in this process, complemented by activation of adhesion molecules that promote leukocyte rolling, tethering and infiltration into the sub-endothelial space. Statins represent the agent of choice since numerous clinical trials have verified that their pharmacological action extends beyond lipid lowering. Statins demonstrate direct anti-oxidant effects by scavenging free radicals and stimulating anti-oxidant enzymes while acting as regulators for cytokine, protein and adhesion molecule expression, all of which are involved in the atherosclerotic process. Statin use is considered one of the most efficient currently used interventions in managing CVD with the likely hood of remaining so in the near future.
    Full-text Article · Mar 2015
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    Vasiliki K. Katsi · Costas T. Psarros · Marios G. Krokidis · [...] · Ioannis E. Kallikazaros
    [Show abstract] [Hide abstract] ABSTRACT: The process involving new blood vessel sprouting from already existing ones is regulated by a physiological complex mechanism, known as angiogenesis. It plays a key role in wound healing but is also present in pathophysiological conditions such as cancer and cardiovascular disease, which have the highest rates of morbidity and mortality worldwide. It is stimulated mechanically or chemically, with the latter involving several signaling pathways and proteins widely known as growth factors. Anti-angiogenesis has always been an appealing target for cardiovascular related diseases, such as atherosclerosis, with its role still eluding our grasp. In this chapter we focus on the latest trends in antiangiogenic therapy and drug discovery as well as highlight the distinct pathways underlying it. Therapies can range from use of peptides, proteins as well as well-defined chemically synthesized molecules. Latest trends involve gene therapy related approaches, with delivery of anti-angiogenic factors to target areas. Furthermore, toxicity issues arising from the use of anti-angiogenic drugs are discussed and highlighted as many of the drugs employed can cause serious side effects, while others may not achieve maximum therapeutic effect. Anti-angiogenic therapy is a very dynamic field and will continue to evolve and improve in the future. A very interesting addition to the anti-angiogenesis drug arsenal can be achieved with the aim of nanotechnology, a novel but promising scientific field. It is certain that in the future new, more potent drugs will be discovered, posing greater therapeutic potential and lower side effects, providing a much needed boost in this continuously evolving scientific field.
    Full-text Article · Jan 2015
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    [Show abstract] [Hide abstract] ABSTRACT: Objective: To explore the role of systemic inflammation in the regulation of adiponectin levels in patients with ischemic heart disease. Approach and results: In a cross-sectional study of 575 subjects, serum adiponectin was compared between healthy subjects, patients with coronary artery disease with no/mild/severe heart failure (HF), and patients with nonischemic HF. Adiponectin expression and release from femoral, subcutaneous and thoracic adipose tissue was determined in 258 additional patients with coronary artery bypass grafting. Responsiveness of the various human adipose tissue depots to interleukin-6, tumor necrosis factor-α, and brain natriuretic peptide (BNP) was examined by using ex vivo models of human fat. The effects of inducible low-grade inflammation were tested by using the model of Salmonella typhi vaccine-induced inflammation in healthy individuals. In the cross-sectional study, HF strikingly increased adiponectin levels. Plasma BNP was the strongest predictor of circulating adiponectin and its release from all adipose tissue depots in patients with coronary artery bypass grafting, even in the absence of HF. Femoral AT was the depot with the least macrophages infiltration and the largest adipocyte cell size and the only responsive to systemic and ex vivo proinflammatory stimulation (effect reversible by BNP). Low-grade inflammation reduced circulating adiponectin levels, while circulating BNP remained unchanged. Conclusions: This study demonstrates the regional variability in the responsiveness of human adipose tissue to systemic inflammation and suggests that BNP (not systemic inflammation) is the main driver of circulating adiponectin in patients with advanced atherosclerosis even in the absence of HF. Any interpretation of circulating adiponectin as a biomarker should take into account the underlying disease state, background inflammation, and BNP levels.
    Full-text Article · Jul 2014 · Arteriosclerosis Thrombosis and Vascular Biology
  • [Show abstract] [Hide abstract] ABSTRACT: Atherosclerosis, the main pathophysiological condition leading to cardiovascular disease (CVD), is now considered to be a chronic inflammatory condition. Statins are the most widely used and promising agents in CVD and are renowned for their pleiotropic lipid lowering independent effects. Statins exert their anti-inflammatory effects on the vascular wall through their implication on a variety of molecular pathways of the innate and adaptive immune system, their impact on the circulating levels of proinflammatory cytokines and their effect on the adhesion molecules. By inhibiting the mevalonate pathway and isoprenoid formation, statins account for the increase of nitric oxide bioavailability and the improvement of vascular and myocardial redox state, by multiple different mechanisms (direct or indirect through LDL lowering). A large number of randomized control trials have well shown that statins help in the primary and secondary prevention of cardiovascular events not only via their lipid lowering effect by due to their anti-inflammatory potential as well. In this article we examine the molecular pathways in which statins are implicated and exert their anti-inflammatory effects, and we are focused specifically in their impact on innate and adaptive immunity. Finally we review the most important clinical data on the role of statins in primary and secondary prevention of cardiovascular events.
    Article · Jun 2014 · Journal of the American College of Cardiology
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    Vasiliki K. Katsi · Costas T. Psarros · Marios G. Krokidis · [...] · Ioannis E. Kallikazaros
    Full-text Book · Jan 2014
  • [Show abstract] [Hide abstract] ABSTRACT: Model asymmetric miktoarm star copolymers of the type AA′B, where A and A′ are polyisoprenes (PIs) and B is deuterated polystyrene (PS), were synthesized by anionic polymerization high-vacuum techniques. Their micellization behavior was studied in n-decane, a selective solvent for the PI blocks, and N,N-dimethylacetamide (DMA), selective for the PS blocks. Utilizing static and dynamic light-scattering techniques along with dilute solution viscometry, parameters such as the aggregation number, Nw, the hydrodynamic and viscometric radii were determined. Based on these results, structural parameters of the micelles, that is, core and corona radii, as well as core-corona interfacial area, were calculated. The thermal stability of the micelles was also examined in both selective solvents. The macromolecular architecture was found to have a considerable effect on the micellization behavior of the block copolymers.
    Article · Jun 2013 · Polymer Journal
  • [Show abstract] [Hide abstract] ABSTRACT: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in developed countries, with an increasing prevalence due to an aging population. The pathology underpinning CVD is atherosclerosis, a chronic inflammatory state involving the arterial wall. Accumulation of low density lipoprotein (LDL) laden macrophages in the arterial wall and their subsequent transformation into foam cells lead to atherosclerotic plaque formation. Progression of atherosclerotic lesions may gradually lead to plaque related complications and clinically manifest as acute vascular syndromes including acute myocardial or cerebral ischemia. Nanotechnology offers emerging therapeutic strategies, which may have advantage overclassical treatments for atherosclerosis. In this review, we present the potential applications of nanotechnology toward prevention, identification and treatment of atherosclerosis.
    Article · Jan 2012 · Maturitas
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    [Show abstract] [Hide abstract] ABSTRACT: The purpose of this study was to evaluate the role of the myocardial redox state in the development of in-hospital complications after cardiac surgery and the effect of statins on the myocardial redox state. Statins improve clinical outcome after cardiac surgery, but it is unclear whether they exert their effects by modifying the myocardial redox state. We quantified myocardial superoxide anion (O(2)(-)) and peroxynitrite (ONOO(-)) and their enzymatic sources in samples of the right atrial appendage (RAA) from 303 patients undergoing cardiac surgery who were followed up until discharge, and in 42 patients who were randomized to receive 3-day treatment with atorvastatin 40 mg/d or placebo before surgery. The mechanisms by which atorvastatin modifies myocardial redox state were investigated in 26 RAA samples that were exposed to atorvastatin ex vivo. Atrial O(2)(-) (derived mainly from nicotinamide adenine dinucleotide phosphate [NADPH] oxidases) and ONOO(-) were independently associated with increased risk of atrial fibrillation, the need for post-operative inotropic support, and the length of hospital stay. Pre-operative atorvastatin treatment suppressed atrial NADPH oxidase activity and myocardial O(2)(-) and ONOO(-) production. Ex vivo incubation of RAA samples with atorvastatin induced a mevalonate-reversible and Rac1-mediated inhibition of NADPH oxidase. There is a strong independent association between myocardial O(2)(-)/ONOO(-) and in-hospital complications after cardiac surgery. Both myocardial O(2)(-) and ONOO(-) are reduced by pre-operative statin treatment, through a Rac1-mediated suppression of NADPH oxidase activity. These findings suggest that inhibition of myocardial NADPH oxidases may contribute to the beneficial effect of statins in patients undergoing cardiac surgery. (Effects of Atorvastatin on Endothelial Function, Vascular and Myocardial Redox State in High Cardiovascular Risk Patients; NCT01013103).
    Full-text Article · Jan 2012 · Journal of the American College of Cardiology
  • [Show abstract] [Hide abstract] ABSTRACT: Treatment with statins improves clinical outcome, but the exact mechanisms of pleiotropic statin effects on vascular function in human atherosclerosis remain unclear. We examined the direct effects of atorvastatin on tetrahydrobiopterin-mediated endothelial nitric oxide (NO) synthase coupling in patients with coronary artery disease. We first examined the association of statin treatment with vascular NO bioavailability and arterial superoxide (O(2)(·-)) in 492 patients undergoing coronary artery bypass graft surgery. Then, 42 statin-naïve patients undergoing elective coronary artery bypass graft surgery were randomized to atorvastatin 40 mg/d or placebo for 3 days before surgery to examine the impact of atorvastatin on endothelial function and O(2)(·-) generation in internal mammary arteries. Finally, segments of internal mammary arteries from 26 patients were used in ex vivo experiments to evaluate the statin-dependent mechanisms regulating the vascular redox state. Statin treatment was associated with improved vascular NO bioavailability and reduced O(2)(·-) generation in internal mammary arteries. Oral atorvastatin increased vascular tetrahydrobiopterin bioavailability and reduced basal and N-nitro-l-arginine methyl ester-inhibitable O(2)(·-) in internal mammary arteries independently of low-density lipoprotein lowering. In ex vivo experiments, atorvastatin rapidly improved vascular tetrahydrobiopterin bioavailability by upregulating GTP-cyclohydrolase I gene expression and activity, resulting in improved endothelial NO synthase coupling and reduced vascular O(2)(·-). These effects were reversed by mevalonate, indicating a direct effect of vascular hydroxymethylglutaryl-coenzyme A reductase inhibition. This study demonstrates for the first time in humans the direct effects of statin treatment on the vascular wall, supporting the notion that this effect is independent of low-density lipoprotein lowering. Atorvastatin directly improves vascular NO bioavailability and reduces vascular O(2)(·-) through tetrahydrobiopterin-mediated endothelial NO synthase coupling. These findings provide new insights into the mechanisms mediating the beneficial vascular effects of statins in humans. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01013103.
    Article · Jul 2011 · Circulation
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    Full-text Article · Apr 2011 · Journal of the American College of Cardiology
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    [Show abstract] [Hide abstract] ABSTRACT: Statins improve clinical outcome of patients with atherosclerosis, but their perioperative role in patients undergoing coronary artery bypass grafting (CABG) is unclear. We hypothesized that short-term treatment with atorvastatin before CABG would improve the redox state in saphenous vein grafts (SVGs), independently of low-density lipoprotein cholesterol (LDL)-lowering. In a randomized, double-blind controlled trial, 42 statin-naïve patients undergoing elective CABG received atorvastatin 40 mg/d or placebo for 3 days before surgery. Circulating inflammatory markers and malondialdehyde (MDA) were measured before and after treatment. SVG segments were used to determine vascular superoxide (O(2)(*-)) and Rac1 activation. For ex vivo studies, SVG segments from 24 patients were incubated for 6 hours with atorvastatin 0, 5, or 50 μmol/L. Oral atorvastatin reduced vascular basal and NADPH-stimulated O(2)(*-) in SVGs (P<0.05 for all versus placebo) and reduced plasma MDA (P<0.05), independently of LDL-lowering and of changes in inflammatory markers. In SVGs exposed to atorvastatin ex vivo, without exposure to LDL, basal and NADPH-stimulated O(2)(·-) were significantly reduced (P<0.01 for both concentrations versus 0 μmol/L) in association with a striking reduction in Rac1 activation and 1 membrane-bound Rac1 and p67(phox) subunit. The antioxidant effects of atorvastatin were reversed by mevalonate, implying a dependence on vascular HMG-CoA reductase inhibition. Short-term treatment with atorvastatin 40 mg/d before CABG improves redox state in SVGs, by inhibiting vascular Rac1-mediated activation of NADPH-oxidase. These novel findings suggest that statin therapy should be maintained or initiated in patients undergoing CABG, independently of LDL levels. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01013103.
    Full-text Article · Sep 2010 · Circulation
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    Full-text Article · Mar 2010 · Journal of the American College of Cardiology
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    Full-text Article · Mar 2010 · Journal of the American College of Cardiology
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    Full-text Article · Mar 2010 · Journal of the American College of Cardiology
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    Full-text Article · Mar 2010 · Journal of the American College of Cardiology
  • [Show abstract] [Hide abstract] ABSTRACT: It is now widely accepted that redox signaling is a key feature in vascular homeostasis. Reactive oxygen species are generated by a wide range of enzymatic systems located in both vascular endothelium and vascular wall. Further, to their role as cytotoxic molecules produced by immune system, free radicals play critical signaling roles in the vascular wall. By regulating several redox-sensitive transcription pathways, free radicals play a key role in the synthesis of inflammatory mediators in both vascular endothelium and vascular wall, with important role in the overall vascular dysfunction. The well-established role of redox state in vascular disease mandates that development of newer therapeutic strategies should be able to alter redox-sensitive intracellular signaling events. Widely used cardiovascular agents like statins or angiotensin receptor blockers have well documented beneficial effects on vascular redox state, reflected also in clinical outcome improvement. Newer promising strategies along with recent patented inventions may also include thiazolidinediones, folates, tetrahydrobiopterin, cyclopentone prostaglandins and aldose reductase inhibitors with well known effects on vascular redox, but with still unclear results on clinical outcome. Better understanding of redox-sensitive intracellular signaling pathways could indicate the critical steps to intervene with newer agents to reverse vascular dysfunction, inhibiting atherosclerosis progression and potentially improve clinical outcome.
    Article · Jul 2009