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Pathophysiological Implications (pathophysiological + implication)
Selected AbstractsSupercomplex organization of the mitochondrial respiratory chain and the role of the Coenzyme Q pool: Pathophysiological implicationsBIOFACTORS, Issue 1-4 2005Maria Luisa Genova Abstract In this review we examine early and recent evidence for an aggregated organization of the mitochondrial respiratory chain. Blue Native Electrophoresis suggests that in several types of mitochondria Complexes I, III and IV are aggregated as fixed supramolecular units having stoichiometric proportions of each individual complex. Kinetic evidence by flux control analysis agrees with this view, however the presence of Complex IV in bovine mitochondria cannot be demonstrated, presumably due to high levels of free Complex. Since most Coenzyme Q appears to be largely free in the lipid bilayer of the inner membrane, binding of Coenzyme Q molecules to the Complex I-III aggregate is forced by its dissociation equilibrium; furthermore free Coenzyme Q is required for succinate-supported respiration and reverse electron transfer. The advantage of the supercomplex organization is in a more efficient electron transfer by channelling of the redox intermediates and in the requirement of a supramolecular structure for the correct assembly of the individual complexes. Preliminary evidence suggests that dilution of the membrane proteins with extra phospholipids and lipid peroxidation may disrupt the supercomplex organization. This finding has pathophysiological implications, in view of the role of oxidative stress in the pathogenesis of many diseases. [source] Endothelin attenuates endothelium-dependent platelet inhibition in manACTA PHYSIOLOGICA, Issue 4 2010R. E. Malmström Abstract Aim:, The vascular endothelium produces several substances, including nitric oxide (NO) and endothelin-1 (ET-1), which participate in the regulation of vascular tone in humans. Both these substances may exert other actions of importance for cardiovascular disease, e.g. effects on vascular smooth muscle cell proliferation and inflammation, and NO inhibits platelet function. Experiments were designed to investigate the effect of ET-1 on endothelium-dependent vasodilatation and attenuation of platelet activation. Methods:, In 25 healthy male subjects (25 ± 1 years), forearm blood flow was measured by venous occlusion plethysmography, and platelet activity was assessed by whole blood flow cytometry (platelet fibrinogen binding and P-selectin expression) in unstimulated and adenosine diphosphate (ADP)-stimulated samples during administration of ET-1, the endothelium-dependent vasodilator acetylcholine and the NO synthase inhibitor l -NMMA. Results:, Acetylcholine increased forearm blood flow and significantly inhibited platelet activation in both unstimulated and ADP-stimulated samples. In samples stimulated with 0.3 ,m ADP, fibrinogen binding decreased from 41 ± 4% to 31 ± 3% (P < 0.01, n = 11) after acetylcholine administration. The vasodilator response to acetylcholine was significantly impaired during infusions of ET-1 and l -NMMA. ET-1 did not affect platelet activity per se, whereas l -NMMA increased platelet P-selectin expression. Both ET-1 and l -NMMA attenuated the acetylcholine-induced inhibition of platelet activity. Conclusions:, Our study indicates that, further to inhibiting endothelium-dependent vasodilatation, ET-1 may also attenuate endothelium-dependent inhibition of platelet activation induced by acetylcholine. An enhanced ET-1 activity, as suggested in endothelial dysfunction, may affect endothelium-dependent platelet modulation and thereby have pathophysiological implications. [source] Homologous desensitization of guanylyl cyclase A, the receptor for atrial natriuretic peptide, is associated with a complex phosphorylation patternFEBS JOURNAL, Issue 11 2010Juliane Schröter Atrial natriuretic peptide (ANP), via its guanylyl cyclase A (GC-A) receptor and intracellular guanosine 3,,5,-cyclic monophosphate production, is critically involved in the regulation of blood pressure. In patients with chronic heart failure, the plasma levels of ANP are increased, but the cardiovascular actions are severely blunted, indicating a receptor or postreceptor defect. Studies on metabolically labelled GC-A-overexpressing cells have indicated that GC-A is extensively phosphorylated, and that ANP-induced homologous desensitization of GC-A correlates with receptor dephosphorylation, a mechanism which might contribute to a loss of function in vivo. In this study, tandem MS analysis of the GC-A receptor, expressed in the human embryonic kidney cell line HEK293, revealed unambiguously that the intracellular domain of the receptor is phosphorylated at multiple residues: Ser487, Ser497, Thr500, Ser502, Ser506, Ser510 and Thr513. MS quantification based on multiple reaction monitoring demonstrated that ANP-provoked desensitization was accompanied by a complex pattern of receptor phosphorylation and dephosphorylation. The population of completely phosphorylated GC-A was diminished. However, intriguingly, the phosphorylation of GC-A at Ser487 was selectively enhanced after exposure to ANP. The functional relevance of this observation was analysed by site-directed mutagenesis. The substitution of Ser487 by glutamate (which mimics phosphorylation) blunted the activation of the GC-A receptor by ANP, but prevented further desensitization. Our data corroborate previous studies suggesting that the responsiveness of GC-A to ANP is regulated by phosphorylation. However, in addition to the dephosphorylation of the previously postulated sites (Ser497, Thr500, Ser502, Ser506, Ser510), homologous desensitization seems to involve the phosphorylation of GC-A at Ser487, a newly identified site of phosphorylation. The identification and further characterization of the specific mechanisms involved in the downregulation of GC-A responsiveness to ANP may have important pathophysiological implications. Structured digital abstract ,,MINT-7713870, MINT-7713887: PMCA (uniprotkb:P20020) and GC-A (uniprotkb:P18910) colocalize (MI:0403) by fluorescence microscopy (MI:0416) [source] The Trigeminal Vasculature Pathology in Patients With NeuralgiaHEADACHE, Issue 9 2007Slobodan Marinkovi Objective.,To examine the possible pathological changes of the trigeminal vasculature in patients with neuralgia. Background.,Such a study has never been performed before. The alterations of the trigeminal vessels could have important pathophysiological implications in the trigeminal neuralgia pathogenesis. Methods.,The biopsy specimens for the electronmicroscopic (EM) and immunohistochemical examination were taken during a partial rhizotomy in 6 patients with trigeminal neuralgia and in 2 persons with trigeminal neuropathy. In addition, the 32 normal trigeminal nerves were used as the control specimens. Results.,The vascular pathological alterations were noticed in 3 out of 6 neuralgia patients. The EM study revealed signs of apoptosis or degeneration, respectively, of some endothelial and smooth muscle cells in the wall of the trigeminal arterioles. The immune reactions against CD31, CD34, and ,-smooth muscle actin in these cells were weaker than in the control specimens, but stronger against factor VIII. In addition, the arteriolar basement membranes, which were thickened, showed an intense laminin, fibronectin, and collagen IV immunoreactivity. Similarly, some endothelial cells and pericytes of the intratrigeminal capillaries also showed signs of apoptosis or degeneration, respectively. Their basement membrane was very thick and showed an intense immune reaction against laminin, fibronectin, and collagen IV. Conclusion.,The observed pathological changes of the trigeminal vasculature could be the primary factor, while demyelination of the trigeminal nerve fibers could be the secondary process in some patients with neuralgia. [source] Update on peptidylarginine deiminases and deimination in skin physiology and severe human diseasesINTERNATIONAL JOURNAL OF COSMETIC SCIENCE, Issue 3 2007M.-C. Méchin Synopsis Deimination (or citrullination) is a recently described post-translational modification, but its consequences are not yet well understood. It is catalysed by peptidylarginine deiminases (PADs). These enzymes transform arginyl residues involved in a peptidyl link into citrullyl residues in a calcium-dependent manner. Several PAD substrates have already been identified like filaggrin and keratins K1 and K10 in the epidermis, trichohyalin in hair follicles, but also ubiquitous proteins like histones. PADs act in a large panel of physiological functions as cellular differentiation or gene regulation. It has been suggested that deimination plays a role in many major diseases such as rheumatoid arthritis, multiple sclerosis, Alzheimer's disease and psoriasis. Five human genes (PADIs), encoding five highly conserved paralogous enzymes (PAD1-4 and 6), have been characterized. These genes are clustered in a single locus, at 1p35-36 in man. Only PAD1-3 are expressed in human epidermis. PADs seem to be controlled at transcriptional, translational and activity levels and they present particular substrate specificities. In this review, we shall discuss these main biochemical, genetic and functional aspects of PADs together with their pathophysiological implications. Résumé La désimination (ou citrullination) est une modification post-traductionnelle catalysée par les peptidyl-arginine désiminases (PADs), décrite depuis peu et dont les conséquences sont encore mal comprises. Ces enzymes transforment, de façon dépendante du calcium, les résidus arginyl engagés dans un lien peptidique en résidus citrullyl. Plusieurs substrats ont été identifiés: la filaggrine et les cytokératines K1 et K10 de l'épiderme, la trichohyaline dans le follicule pileux mais aussi des protéines ubiquistes comme les histones. Les PADs interviennent dans de nombreuses fonctions physiologiques telles que la différenciation cellulaire ou la régulation génique. La désimination pourrait jouer un rôle dans plusieurs maladies sévères et fréquentes comme la polyarthrite rhumatoïde, la sclérose en plaque, la maladie d'Alzheimer ou encore le psoriasis. Cinq gènes humains (PADIs) codant pour 5 enzymes paralogues conservées (PAD1-4 et 6) ont été caractérisés. Ils sont regroupés en un seul locus, en 1p35-36 chez l'homme. Seules les PAD1-3 sont exprimées dans l'épiderme humain. Les PADs semblent contrôlées aux niveaux transcriptionnel et traductionnel, ainsi qu'au niveau de leur activité. Elles présentent chacune leurs spécificités de substrats. Ces principaux aspects biochimiques, génétiques et fonctionnels des PADs tout comme leurs implications physiopathologiques seront discutés dans cette revue. [source] Missing link identified: GpBAR1 is a neuronal bile acid receptorNEUROGASTROENTEROLOGY & MOTILITY, Issue 7 2010S. J. Keely Abstract,In addition to their classical functions in aiding the digestion and absorption of lipids, bile acids are increasingly gaining appreciation for their roles in regulating intestinal physiology. Bile acids are now widely considered as hormones that exert a wide range of physiological and pathophysiological effects both within and outside the gastrointestinal (GI) tract. The discovery of the bile acid receptor, GpBAR1, represented a major step forward in our understanding of how cells can sense and respond to bile acids. GpBAR1 is a cell surface G protein-coupled receptor expressed on adipose tissue and skeletal muscle where it has been found to be an important regulator of cellular metabolism. In a paper published in the current issue of Neurogastroenterology and Motility, Poole et al. investigated the expression and function of GpBAR1 in mouse intestine. They found the receptor to be expressed throughout the GI tract but predominantly on nerves within the myenteric and submucosal plexuses. Employing in vitro and in vivo techniques they demonstrated that activation of GpBAR1 by bile acids inhibits small and large intestinal motor function and delays intestinal transit. The effects of GpBAR1 activation are mediated through activation of cholinergic and nitrergic interneurons. The data reported by Poole et al. provides novel and exciting insights into how bile acids exert their actions in the intestine. This Editorial Viewpoint aims to further consider the potential physiological and pathophysiological implications of their findings. [source] Dissociated Activity and Pulmonary Vein Fibrillation Following Functional Disconnection:PACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 6 2003Impact for the Arrhythmogenesis of Focal Atrial Fibrillation The present study sought to investigate the electrophysiological properties of isolated pulmonary veins following successful radiofrequency (RF) catheter ablation in patients with paroxysmal atrial fibrillation (PAF). Overall, 71 pulmonary veins in 37 consecutive patients (age:56 ± 9 years) with recurrent PAF were targeted for RF ablation at the ostial region in order to achieve a complete functional block. Following disconnection, the incidence of dissociated pulmonary vein (PV) activity and its response to orciprenalin were studied. RF ablation abolished conduction in 67 (94%) of 71 potentially arrhythmogenic PVs after a mean of10.7 ± 6.4 RFapplications for each PV. After ablation, spontaneous dissociated automatic activity (9 to 52 beats/min, median 27) was found in 6 out of 67 isolated PVs (left superior:n = 1, left inferior:n = 1, right superior:n = 2, common left PV:n = 2). Slight acceleration (13 to 68 beats/min, median 29) of dissociated PV activity was observed during infusion of orciprenalin. Following isolation, initiation of sustained or nonsustained local fibrillation was recorded in only two cases of the common left sided PV with preceding automatic activity. In one patient PV fibrillation occurred during orciprenalin infusion following a repetitive response to a dissociated automatic rhythm with increasing duration as well as destabilization. In the other patient, PV fibrillation occurred immediately after the occurrence of PV automaticity. Slow dissociated automatic rhythms are detectable within 9% of disconnected PVs. The unique anatomic substrate of common left PVs seem to favor the occurrence of local fibrillation following isolation. The initiation pattern of fibrillation within the isolated PV has pathophysiological implications and underlines the contribution of multiple factors to the onset and sustenance of PAF. (PACE 2003; 26:1363,1370) [source] Reductions in basal limb blood flow and vascular conductance with human ageing: role for augmented ,-adrenergic vasoconstrictionTHE JOURNAL OF PHYSIOLOGY, Issue 3 2001Frank A. Dinenno 1Basal whole-limb blood flow and vascular conductance decrease with age in men. We determined whether these age-associated changes in limb haemodynamics are mediated by tonically augmented sympathetic ,-adrenergic vasoconstriction. 2Seven young (28 ± 2 years; mean ±s.e.m.) and eight older (64 ± 2 years) healthy, normotensive adult men were studied. Baseline femoral artery blood flow (Doppler ultrasound) and calculated vascular conductance were 29 and 31 % lower, respectively, and vascular resistance was 53 % higher in the older men (all P < 0.001). 3Local (intra-femoral artery) ,-adrenergic receptor blockade with phentolamine evoked greater increases in femoral blood flow (105 ± 11 vs. 60 ± 6 %) and vascular conductance (125 ± 13 vs. 66 ± 7 %), and reductions in vascular resistance (55 ± 2 vs. 39 ± 3 %) in the experimental limb of the older compared with the young men (all P < 0.001). As a result, ,-adrenergic receptor blockade eliminated the significance of the age-associated differences in absolute levels of femoral blood flow (500 ± 51 vs. 551 ± 35 ml min,1), vascular conductance (6.02 ± 0.73 vs. 6.33 ± 0.26 U), and vascular resistance (0.17 ± 0.03 vs. 0.16 ± 0.01 U; P= 0.4,0.8, n.s.). Femoral haemodynamics in the control limb were unaffected by phentolamine administration in the contralateral (experimental) limb. Complete ,-adrenergic receptor blockade was demonstrated by the absence of vasoconstriction in the experimental limb in response to the cold pressor test. Local propranolol was administered to control for any ,-adrenergic effects of phentolamine. Propranolol did not affect haemodynamics in the experimental or control limbs. 4Our results indicate that the age-related reductions in basal limb blood flow and vascular conductance are mediated largely by chronically elevated sympathetic ,-adrenergic vasoconstriction. This may have important physiological and pathophysiological implications for the ageing human. [source] Supercomplex organization of the mitochondrial respiratory chain and the role of the Coenzyme Q pool: Pathophysiological implicationsBIOFACTORS, Issue 1-4 2005Maria Luisa Genova Abstract In this review we examine early and recent evidence for an aggregated organization of the mitochondrial respiratory chain. Blue Native Electrophoresis suggests that in several types of mitochondria Complexes I, III and IV are aggregated as fixed supramolecular units having stoichiometric proportions of each individual complex. Kinetic evidence by flux control analysis agrees with this view, however the presence of Complex IV in bovine mitochondria cannot be demonstrated, presumably due to high levels of free Complex. Since most Coenzyme Q appears to be largely free in the lipid bilayer of the inner membrane, binding of Coenzyme Q molecules to the Complex I-III aggregate is forced by its dissociation equilibrium; furthermore free Coenzyme Q is required for succinate-supported respiration and reverse electron transfer. The advantage of the supercomplex organization is in a more efficient electron transfer by channelling of the redox intermediates and in the requirement of a supramolecular structure for the correct assembly of the individual complexes. Preliminary evidence suggests that dilution of the membrane proteins with extra phospholipids and lipid peroxidation may disrupt the supercomplex organization. This finding has pathophysiological implications, in view of the role of oxidative stress in the pathogenesis of many diseases. [source] Ghrelin: more than a natural GH secretagogue and/or an orexigenic factorCLINICAL ENDOCRINOLOGY, Issue 1 2005E. Ghigo Summary Ghrelin, an acylated peptide produced predominantly by the stomach, has been discovered to be a natural ligand of the growth hormone secretagogue receptor type 1a (GHS-R1a). Ghrelin has recently attracted considerable interest as a new orexigenic factor. However, ghrelin exerts several other neuroendocrine, metabolic and also nonendocrine actions that are explained by the widespread distribution of ghrelin and GHS-R expression. The likely existence of GHS-R subtypes and evidence that the neuroendocrine actions, but not all the other actions, of ghrelin depend on its acylation in serine-3 revealed a system whose complexity had not been completely explored by studying synthetic GHS. Ghrelin secretion is mainly regulated by metabolic signals and, in turn, the modulatory action of ghrelin on the control of food intake and energy metabolism seems to be among its most important biological actions. However, according to a recent study, ghrelin-null mice are neither anorectics nor dwarfs and this evidence clearly depicts a remarkable difference from leptin null mice. Nevertheless, the original and fascinating story of ghrelin, as well as its potential pathophysiological implications in endocrinology and internal medicine, is not definitively cancelled by these data as GHS-R1a null aged mice show significant alterations in body composition and growth, in glucose metabolism, cardiac function and contextual memory. Besides potential clinical implications for natural or synthetic ghrelin analogues acting as agonists or antagonists, there are several open questions awaiting an answer. How many ghrelin receptor subtypes exist? Is ghrelin ,the' or just ,a' GHS-R ligand? That is, are there other natural GHS-R ligands? Is there a functional balance between acylated and unacylated ghrelin forms, potentially with different actions? Within the next few years suitable answers to these questions will probably be found, making it possible to gain a better knowledge of ghrelin's potential clinical perspectives. [source] | |||||||||||||