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Basic Science

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Simply say yes to NO? Nitric oxide (NO) sensor-based assessment of coronary endothelial function - Figure 1

Eur. Heart J. (2010), 31 (23), 2834-2836; 10.1093/eurheartj/ehq279 - Click here to view abstract

llustration of the stimulation of endothelial NO synthase by acetylcholine and shear stress leading to increased nitric oxide (NO) production in endothelial cells by receptor and non-receptor and calcium-dependent and non-calcium-dependent pathways. NO diffuses abluminally and luminally with the indicated effects. In the presence of endothelial cell dysfunction, acetylcholine acts on vascular smooth muscle cells directly causing constriction and does not provoke as much of an NO release into the main lumen. Vasoconstriction increases shear stress, the most potent physiological stimulus for NO production. However, a dysfunctional endothelial cell will not respond with as much NO production.

Inflammatory cytokines in heart failure: roles in aetiology and utility as biomarkers - Figure 1

Eur. Heart J. (2010), 31 (7), 768-770; 10.1093/eurheartj/ehq014 - Click here to view abstract

Effects of the interleukin-6 cytokine family on myocardial fibroblasts and myocytes. The figure shows the potential cellular mechanisms of interleukin-6 signalling within myocardial fibroblasts (A) and myocytes (B). Within the fibroblast, IL-6 facilitates the migration and proliferation of fibroblasts and increases the production of collagen and IL-6 receptors leading to remodelling. Within myocytes, the IL-6 receptor is linked to GP130, and the downstream signalling cascade can promote myocyte hypertrophy (via JAK), apoptosis (via MAPK), and up-regulation of inducible nitric oxide synthase (via PI3K). IL-6 also increases the expression of xanthine oxidase and NADPH oxidase mRNA. The production of superoxide and nitric oxide can increase the production of peroxynitrite (ONOO−), which in turn can lead to depressed contractility by adversely influencing excitation–contraction coupling through effects on SERCA2a and possibly the ryanodine receptor (RYR). Peroxynitrite also causes DNA damage and increases the expression of IL-6 receptors. MAPK, mitogen activated protein kinase; JAK, Janus Kinase; PI3K, Phosphoinositide 3 kinase; SERCA, Sarcoplasmic reticulum calcium ATPase; XO, xanthine oxidase; PLB, phospholamban; iNOS, inducible nitric oxide synthase; RYR, ryanodine receptor.


Depression, anxiety, and platelet reactivity in patients with coronary heart disease - Figure 1

Eur. Heart J. (2010), 31 (13), 1548-1550; 10.1093/eurheartj/ehq097 - Click here to view abstract

Illustration of a potential pathway linking serotonin to enhanced platelet activation in patients with anxiety. Anxiety and other forms of psychological stress are perceived in the cerebral cortex, and activating signals are sent via the hypothalamus to sympathetic preganglionic neurons in the spinal cord. Preganglionic sympathetic stimulation of chromaffin cells in the adrenal medulla results in release of catecholamines, primarily epinephrine (EPI), into the circulation. Epinephrine binds to the α2A receptor on circulating platelets and stimulates other platelet agonists such as ADP. These platelet agonists result in the mobilization of intracellular calcium ([Ca2+]) which causes conformational shape change of the platelet and expression of the glycoprotein IIb/IIIa receptor (GPIIb-IIIa). Increased intracellular calcium also leads to degranulation of alpha (α) and dense (δ) granules. The α granules release a variety of adhesive proteins and prothrombotic and inflammatory factors. The δ granules store serotonin (5-HT) and release it along with other platelet agonists such as ADP and ATP. Once released, serotonin can be taken back up by the serotonin transporter (SERT) to be stored once again in δ granules, or it can bind to the serotonin receptor (5-HT2AR). Binding of serotonin to its receptor results in further calcium mobilization and degranulation, thus enhancing the activation of neighbouring platelets in an evolving thrombus.

microRNAs in heart disease: putative novel therapeutic targets? - Figure 1

Eur. Heart J. (2010), 31 (6), 649-658; 10.1093/eurheartj/ehp573 - Click here to view abstract

Schematic of microRNA biogenesis and action. See text for explanation. The mature microRNA sequence is given in red. TF, transcription factor; Pol, RNA polymerase II or III; Exp5, exportin 5.

microRNAs in heart disease: putative novel therapeutic targets? - Figure 2

Eur. Heart J. (2010), 31 (6), 649-658; 10.1093/eurheartj/ehp573 - Click here to view abstract

Schematic overview of strategies used to alter microRNA expression. (A) Cells express a microRNA profile that can become altered with disease. Antisense oligonucleotides, such as antagomirs, sponges, and erasers (in red) can capture microRNAs for knockdown or sequestrate inappropriately overexpressed microRNAs, whereas artificially introduced microRNAs (in red) can be used to overexpress microRNAs or, potentially, to replace expression of downregulated ones. These strategies have the potential to affect large numbers of different targets (for simplicity, only one target mRNA per microRNA is represented). (B) Masks and gene-specific microRNA mimics (in red) can be used to affect single targets specifically (mRNAs in different shades of blue represent a set affected by a given microRNA).


Redox biomarkers in cardiovascular medicine

Eur. Heart J. (2015), 36 (25), 1576-1582, Fig 1; 10.1093/eurheartj/ehv126 - click here to view abstract

Compartmentalized redox signalling and their relationship to circulating biomarkers. The biomarkers measured in the blood are shown in boxes. The levels of oxidation products, cellular antioxidant enzymes, and sources of reactive oxygen species measured in circulation depend on the kinetics of release, retention and clearance, thus may not fully reflect redox homeostasis at the level of cells and tissues, in particular in membrane signalling microdomains (caveolae, inset). As an example of a strategy to circumvent such issues, neurohormone-mediated S-glutathionylation of Na+–K+ pump in red blood cells is shown. Based on our preliminary data, these pathways reflect the redox signalling in cardiac myocytes, with the levels of pump S-glutathionylation closely paralleling the levels in myocytes in heart failure. MPO, myeloperoxidase; SOD, superoxide dismutase; CAT, catalase; GPX, glutathione peroxidase; OxLDL, oxidized low-density lipoprotein; 8-OHdG, 8-hydroxy-2′deoxyguanosine; sNOX2-dp, soluble NOX2-derived peptide.


Redox biomarkers in cardiovascular medicine

Eur. Heart J. (2015), 36 (25), 1576-1582, Fig 2; 10.1093/eurheartj/ehv126 - click here to view abstract

Oxidative biomarkers as potential ‘integrators’ of cardiovascular risk factors. The downstream effector role of oxidative signalling in a broad range of conditions predisposing to cardiovascular disease places them as excellent candidates to reflect the integrated effects of many known and potentially unknown risk factors. The demonstrated effects of pharmacotherapies [e.g. angiotensin-converting enzyme inhibitors, statins and β-blockers] on redox biomarkers suggest that they may be early indicators of the efficacy of pharmacotherapy in a particular patient, and thus be useful in choosing selective treatment in patients not tolerating combined therapies.


Redox biomarkers in cardiovascular medicine

Eur. Heart J. (2015), 36 (25), 1576-1582, Fig 3; 10.1093/eurheartj/ehv126 - click here to view abstract

Biomarkers and their respective developmental milestones on their path from discovery to clinical application. The progress of each biomarker is represented by the relative location of the schematic runners. The strength of the current evidence for each biomarker in cardiovascular disease is discussed in the adjacent text boxes. Despite great progress in redox biology field, no biomarker is currently in widespread clinical use.


Mitochondrial disorders with cardiac dysfunction: an under-reported aetiology with phenotypic heterogeneity

Eur. Heart J. (2014), 36 (42), -, Fig 1; 10.1093/eurheartj/ehv429 - click here to view abstract

A multidisciplinary approach to diagnose and treat mitochondrial disease.


Nox4 NADPH Oxidase: Emerging from the veil of darkness

Eur. Heart J. (2015), 36 (48), -, Fig 1; 10.1093/eurheartj/ehv518 - click here to view abstract

Vascular NADPH oxidase (Nox)-derived reactive oxygen species modulate the balance between pro- and antiatherogenic processes in the vascular wall. eNOS, endothelial nitric oxide synthase; O2·, superoxide anion; ONOO–, peroxynitrite; NO·, nitric oxide; H2O2, hydrogen peroxide; SOD, superoxide dismutase.

C1q/TNF-related protein 1: a novel link between visceral fat and athero-inflammation

Eur. Heart J. (2016) 37(22) doi: 10.1093/eurheartj/ehv754 - Click here to view the abstract

The adipokine CTRP1 (C1q/tumour necrosis factor-related protein 1) is produced in adipose tissue (yellow area) as well by oxidized LDL (OxLDL)- or interleukin-1β (IL-1β)-stimulated macrophages and endothelial cells in the atherosclerotic plaque (purple area). In the plaque, CTRP1 activates endothelial cells and macrophages themselves to produce leucocyte adhesion molecules and tumour necrosis factor α (TNFα), which enhance leucocyte entry and inflammatory activation. An increase in CTRP1 levels in blood is associated with increased coronary artery disease risk. Plasma CTRP1 originates from visceral adipose tissue as well as from monocytes and from areas with ongoing inflammation. MAPK, mitogen-acivated protein kinase; NF-κB, nuclear factor-κB; VCAM, vascular cell adhesion molecule; M1, macrophage.

MicroRNAs: small molecule, big potential for coronary artery disease

Eur. Heart J. (2016) 37(22) doi: 10.1093/eurheartj/ehw067 - Click here to view the abstract

Proposed timeline of coronary atherosclerosis and contribution of microRNA (miR) transcoronary gradients (TCGs) at each step. Interestingly, at most stages, miR-126, miR133, and mi-155 appear to be in abundance throughout the disease process, while very few miRs have reduced gradients (or are ‘retained’ in the circulation). ACS, acute coronary syndrome; CAD, coronary artery disease; CED, coronary endothelial dysfunction.

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