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Thomas F. Lüscher
Bernard J. Gersh
Illustration 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.
Effects of the interleukin-6 cytokine family on myocardial fibroblasts and myocytes. The figure shows the potential cellular mechanims 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 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), apoprosis (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 (ONOO2), 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.
Illustration of a potential pathway linking serotonin to enhanced platelet activation in patients with anxiety. Anxiety and other forms of pyschological stress are perceived in the cerebal 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 a2A 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 (a) and dense (d) granules. The a granukes release a variety of adhesive proteins and prothrombotic and inflammatory factors. The d 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 (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.
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.
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).
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