Kegg Pathway: Complement and coagulation cascades

Physiol Genomics. 2008 Jul 15;
Rajasekaran NS, Firpo MA, Milash BA, Weiss RB, Benjamin IJ

Protein aggregation cardiomyopathy is a life-threatening manifestation of a multisystem disorder caused by the exchange mutation in the gene encoding the human small heat shock protein alphaB-crystallin (hR120GCryAB). Genetic studies in mice have established cardiac hR120GCryAB expression causes increased activity of glucose 6-phosphate dehydrogenase (G6PD) and 'reductive stress' (Rajasekeran et al., Cell. 2007;130(3):401-2). However, the initiating molecular events in the pathogenesis of this novel toxic gain-of-function mechanism remain poorly defined. In an integrated systems approach using gene expression profiling, we identified a 'biosignature' whose features can be validated to predict the onset, rate of progression, and clinical outcome of R120GCryAB cardiomyopathy. At the 3 month disease-related but compensated stage, we demonstrate that transcripts were only upregulated in three distinct pathways: stress response (e.g., Hsp70, Hsp90), glutathione metabolism (Gpx1, Gpx3, glutathione S-transferase), and Complement and coagulation cascades in hR120GCryAB transgenic mouse hearts compared with either hCryAB WT transgenic mice or non-transgenic controls. In 6 month old myopathic hearts, ribosomal synthesis and cellular remodeling associated with increased cardiac hypertrophy were additional upregulated pathways. In contrast, the predominant down-regulated pathways were for oxidative phosphorylation, fatty acid metabolism, intermediate metabolism, and energetic balance, supporting their primary pathogenic roles by which G6PD-dependent reductive stress causes cardiac decompensation and overt heart failure in hR120GCryAB cardiomyopathy. This study extends and confirms our previous findings that reductive stress is a causal mechanism for hR120G CryAB cardiomyopathy and demonstrates that alteration in glutathione pathway gene expression is an early biosignature with utility for pre-symptomatic detection. Key words: reductive stress, microarray, transgenic mice, glutathione metabolism.

Eur J Cardiothorac Surg. 2008 Jun 20;
Banz Y, Rieben R, Zobrist C, Meier P, Shaw S, Lanz J, Carrel T, Berdat P

Objective: Contact of blood with artificial surfaces and air as well as ischemia/reperfusion injury to the heart and lungs mediate systemic and local inflammation during cardiopulmonary bypass (CPB). Activation of Complement and coagulation cascades leads to and accompanies endothelial cell damage. Therefore, endothelial-targeted cytoprotection with the Complement inhibitor and endothelial protectant dextran sulfate (DXS, MW 5000) may attenuate CBP-associated myocardial and pulmonary injury. Methods: Eighteen pigs (DXS, n=10; phosphate buffered saline [PBS], n=8) underwent standard cardiopulmonary bypass. After aortic cross-clamping, cardiac arrest was initiated with modified Buckberg blood cardioplegia (BCP), repeated after 30 and 60min with BCP containing either DXS (300mg/10ml, equivalent to 5mg/kg) or 10ml of PBS. Following 30min reperfusion, pigs were weaned from CPB. During 2h of observation, cardiac function was monitored by echocardiography and invasive pressure measurements. Inflammatory and coagulation markers were assessed regularly. Animals were then sacrificed and heart and lungs analyzed. Results: DXS significantly reduced CK-MB levels (43.4+/-14.8ng/ml PBS, 35.9+/-11.1ng/ml DXS, p=0.042) and significantly diminished cytokine release: TNFalpha (1507.6+/-269.2pg/ml PBS, 222.1+/-125.6pg/ml DXS, p=0.0071), IL1beta (1081.8+/-203.0pg/ml PBS, 110.7+/-79.4pg/ml DXS, p=0.0071), IL-6 (173.0+/-91.5pg/ml PBS, 40.8+/-19.4pg/ml DXS, p=0.002) and IL-8 (304.6+/-81.3pg/ml PBS, 25.4+/-14.2pg/ml DXS, p=0.0071). Tissue endothelin-1 levels were significantly reduced (6.29+/-1.90pg/100mg PBS, 3.55+/-1.15pg/100mg DXS p=0.030) as well as thrombin-anti-thrombin formation (20.7+/-1.0mug/ml PBS, 12.8+/-4.1mug/ml DXS, p=0.043). Also DXS reduced cardiac and pulmonary Complement deposition, neutrophil infiltration, hemorrhage and pulmonary edema (measured as lung water content, 81+/-3% vs 78+/-3%, p=0.047), indicative of attenuated myocardial and pulmonary CPB-injury. Diastolic left ventricular function (measured as dp/dt(min)), pulmonary artery pressure (21+/-3mmHg PBS, 19+/-3mmHg DXS, p=0.002) and right ventricular pressure (21+/-1mmHg PBS, 19+/-3mmHg DXS p=0.021) were significantly improved with the use of DXS. Conclusions: Addition of DXS to the BCP solution ameliorates post-CPB injury and to a certain extent improves cardiopulmonary function. Endothelial protection in addition to myocyte protection may improve post-CPB outcome and recovery.

Physiol Genomics. 2008 Jun 10;
Nilsen AJ, Landin MA, Haug KH, Fonnum F, Berger U, Osmundsen H

Pentadecafluorooctanoic acid is an established peroxisome proliferator. Little is known about effects of treatment with 1H, 1H, 2H, 2H-heptadecafluorodecan-1-ol, which is metabolised to pentadecafluorooctanoic acid. We have compared effects of various dosages (3, 10 or 25mg/kg body-wt) of each of these compounds on hepatic gene-expression in rats using microarrays. Microarray data were validated by real-time RT-PCR. Expression data were also correlated with hepatic activities of selected enzymes, and with hepatic levels of pentadecafluorooctanoic acid and 1H, 1H, 2H, 2H-heptadecafluoro-decan-1-ol. Pentadecafluorooctanoic acid caused the more powerful change in gene expression, both in terms of number of genes affected and extents of change in expression. Across the dosages used pentadecafluorooctanoic acid or 1H, 1H, 2H, 2H-heptadecafluorodecan-1-ol caused significant (PComplement and coagulation cascades. Key words: microarray, bioinformatics, liver, perfluorinated compounds.

Lipids Health Dis. 2007; 6: 35
Das UN, Rao AA

Obesity is an important component of metabolic syndrome X and predisposes to the development of type 2 diabetes mellitus. The incidence of obesity, type 2 diabetes mellitus and metabolic syndrome X is increasing, and the cause(s) for this increasing incidence is not clear. Although genetics could play an important role in the higher prevalence of these diseases, it is not clear how genetic factors interact with environmental and dietary factors to increase their incidence. We performed gene expression profile in subjects with obesity and type 2 diabetes mellitus with and without family history of these diseases. It was noted that genes involved in carbohydrate, lipid and amino acid metabolism pathways, glycan of biosynthesis, metabolism of cofactors and vitamin pathways, ubiquitin mediated proteolysis, signal transduction pathways, neuroactive ligand-receptor interaction, nervous system pathways, neurodegenerative disorders pathways are upregulated in obesity compared to healthy subjects. In contrast genes involved in cell adhesion molecules, cytokine-cytokine receptor interaction, insulin signaling and immune system pathways are downregulated in obese. Genes involved in signal transduction, regulation of actin cytoskeleton, antigen processing and presentation, Complement and coagulation cascades, axon guidance and neurodegenerative disorders pathways are upregulated in subjects with type 2 diabetes with family history of diabetes compared to those who are diabetic but with no family history. Genes involved in oxidative phosphorylation, immune, nervous system, and metabolic disorders pathways are upregulated in those with diabetes with family history of diabetes compared to those with diabetes but with no family history. In contrast, genes involved in lipid and amino acid pathways, ubiquitin mediated proteolysis, signal transduction, insulin signaling and PPAR signaling pathways are downregulated in subjects with diabetes with family history of diabetes. It was noted that genes involved in inflammatory pathway are differentially expressed both in obesity and type 2 diabetes. These results suggest that genes concerned with carbohydrate, lipid and amino acid metabolic pathways, neuronal function and inflammation play a significant role in the pathobiology of obesity and type 2 diabetes.

Endocrinology. 2007 Nov; 148(11): 5549-57
Buffat C, Boubred F, Mondon F, Chelbi ST, Feuerstein JM, Lelièvre-Pégorier M, Vaiman D, Simeoni U

In this study, low birth weight was induced in rats by feeding the dams with a low-protein diet during pregnancy. Kidneys from the fetuses at the end of gestation were collected and showed a reduction in overall and relative weight, in parallel with other tissues (heart and liver). This reduction was associated with a reduction in nephrons number. To better understand the molecular basis of this observation, a transcriptome analysis contrasting kidneys from control and protein-deprived rats was performed, using a platform based upon long isothermic oligonucleotides, strengthening the robustness of the results. We could identify over 1800 transcripts modified more than twice (772 induced and 1040 repressed). Genes of either category were automatically classified according to functional criteria, making it possible to bring to light a large cluster of genes involved in coagulation and Complement cascades. The promoters of the most induced and most repressed genes were contrasted for their composition in putative transcription factor binding sites, suggesting an overrepresentation of the AP1R binding site, together with the transcription induction of factors actually binding to this site in the set of induced genes. The induction of coagulation cascades in the kidney of low-birth-weight rats provides a putative rationale for explaining thrombo-endothelial disorders also observed in intrauterine growth-restricted human newborns. These alterations in the kidneys have been reported as a probable cause for cardiovascular diseases in the adult.

Inflammopharmacology. 1999; 7(3): 207-17
Ginsburg I

-The paper discusses the principal evidence that supports the concept that cell and tissue injury in infectious and post-infectious and inflammatory sequelae might involve a deleterious synergistic interaction among microbial- and host-derived pro-inflammatory agonists. Experimental models had proposed that a rapid cell and tissue injury might be induced by combinations among subtoxic amounts of three major groups of agonists generated both by microorganisms and by the host's own defense systems. These include: (1) oxidants: Superoxide, H(2)O(2), OH', oxidants generated by xanthine-xanthine-oxidase, ROO; HOC1, NO, OONO'-, (2) the membrane-injuring and perforating agents, microbial hemolysins, phospholipases A(2) and C, lysophosphatides, bactericidal cationic proteins, fatty acids, bile salts and the attack complex of Complement a, certain xenobics and (3) the highly cationic proteinases, elastase and cathepsin G, as well as collagenase, plasmin, trypsin and a variety of microbial proteinases. Cell killing by combinations among the various agonists also results in the release of membrane-associated arachidonate and metabolites. Cell damage might be further enhanced by certain cytokines either acting directly on targets or through their capacity to prime phagocytes to generate excessive amounts of oxidants. The microbial cell wall components, lipoteichoic acid (LTA), lipopolysaccharides (LPS) and peptidoglycan (PPG), released following bacteriolysis, induced either by cationic proteins from neutrophils and eosinophils or by beta lactam antibiotics, are potent activators of macrophages which can release oxidants, cytolytic cytokines and NO. The microbial cell wall components can also activate the cascades of coagulation, Complement and fibrinolysis. All these cascades might further synergize with microbial toxins and metabolites and with phagocyte-derived agonsits to amplify tissue damage and to induce septic shock, multiple organ failure, 'flesh-eating' syndromes, etc. The long persistence of non-biodegradable bacterial cell wall components within activated macrophages in granulomatous inflammation might be the result of the inactivation by oxidants and proteinases of bacterial autolytic wall enzymes (muramidases). The unsuccessful attempts in recent clinical trials to prevent septic shock by the administration of single antagonists is disconcerting. It does suggest however that, since tissue damage in post-infectious syndromes is most probably the end result of synergistic interactions among a multiplicity of agents, only agents which might depress bacteriolysis in vivo and 'cocktails' of appropriate antagonists, but not single antagonists, if administered at the early phases of infection especially to patients at high risk, might help to control the development of post-infectious syndromes. However, the use of adequate predictive markers for sepsis and other post-infectious complications is highly desirable. Although it is conceivable that anti-inflammatory strategies might also be counter-productive as they might act as 'double-edge swords', intensive investigations to devise combination therapies are warranted. The present review also lists the major anti-inflammatory agents and strategies and combinations among them which have been proposed in the last few years for clinical treatments of sepsis and other post-infectious complications.

Genome Biol. 2007; 8(6): R121
Itoh M, Nacher JC, Kuma K, Goto S, Kanehisa M

BACKGROUND: In higher multicellular eukaryotes, complex protein domain combinations contribute to various cellular functions such as regulation of intercellular or intracellular signaling and interactions. To elucidate the characteristics and evolutionary mechanisms that underlie such domain combinations, it is essential to examine the different types of domains and their combinations among different groups of eukaryotes. RESULTS: We observed a large number of group-specific domain combinations in animals, especially in vertebrates. Examples include animal-specific combinations in tyrosine phosphorylation systems and vertebrate-specific combinations in Complement and coagulation cascades. These systems apparently underwent extensive evolution in the ancestors of these groups. In extant animals, especially in vertebrates, animal-specific domains have greater connectivity than do other domains on average, and contribute to the varying number of combinations in each animal subgroup. In other groups, the connectivities of older domains were greater on average. To observe the global behavior of domain combinations during evolution, we traced the changes in domain combinations among animals and fungi in a network analysis. Our results indicate that there is a correlation between the differences in domain combinations among different phylogenetic groups and different global behaviors. CONCLUSION: Rapid emergence of animal-specific domains was observed in animals, contributing to specific domain combinations and functional diversification, but no such trends were observed in other clades of eukaryotes. We therefore suggest that the strategy for achieving complex multicellular systems in animals differs from that of other eukaryotes.

Trends Immunol. 2007 Apr; 28(4): 184-92
Markiewski MM, Nilsson B, Ekdahl KN, Mollnes TE, Lambris JD

The convergence between Complement and the clotting system extends far beyond the chemical nature of the Complement and coagulation components, both of which form proteolytic cascades. Complement effectors directly enhance coagulation. These effects are supplemented by the interactions of Complement with other inflammatory mediators that can increase the thrombogenicity of blood. In addition, Complement inhibits anticoagulant factors. The crosstalk between Complement and coagulation is also well illustrated by the ability of certain coagulation enzymes to activate Complement components. Understanding the interplay between Complement and coagulation has fundamental clinical implications in the context of diseases with an inflammatory pathogenesis, in which Complement-coagulation interactions contribute to the development of life-threatening complications. Here, we review the interactions of the Complement system with hemostasis and their roles in various diseases.

J Clin Invest. 2007 Mar; 117(3): 595-8
Reilly MP, Tall AR

In this issue of the JCI, Vaisar et al. studied the proteome of HDL (see the related article beginning on page 746). They reveal, quite unexpectedly, that HDL is enriched in several proteins involved in the Complement cascade, as well as in a variety of protease inhibitors, supporting the concept that HDL plays a role in innate immunity and in the regulation of proteolytic cascades involved in inflammatory and coagulation processes. The protein makeup of HDL also appears to be altered in patients with coronary artery disease. HDL proteomics is in its infancy, and preliminary findings will need to be confirmed using standardized approaches in larger clinical samples. However, this approach promises to better elucidate the relationship of HDL to atherosclerosis and its complications and could eventually help in the development of biomarkers to predict the outcome of interventions that alter HDL levels and functions.

Transpl Int. 2007 Feb; 20(2): 107-17
Tai HC, Ezzelarab M, Hara H, Ayares D, Cooper DK

The production of alpha1,3-galactosyltransferase gene-knockout (GT-KO) pigs has overcome the barrier of preformed anti-Galalpha1,3Gal (Gal) antibodies that has inhibited progress in pig-to-primate organ xenotransplantation for many years. Survival of GT-KO pig organs in nonhuman primates is currently limited by the development of a thrombotic microangiopathy that results in increasing ischemic injury of the transplanted organ over weeks or months. Potential causative factors include vascular endothelial activation from preformed anti-nonGal antibodies or cells of the innate immune system that recognize nonGal pig antigens directly, and coagulation dysregulation associated with molecular incompatibilities between pig and primate. Carefully isolated pancreatic islets from wild-type (genetically unmodified) adult pigs express minimal Gal epitopes, allowing survival sometimes for weeks or m