The HLA locus is the strongest risk factor for anti-citrullinated protein antibody (ACPA)(+) rheumatoid arthritis (RA). Despite considerable efforts in the last 35 years, this association is poorly ...understood. Here we identify (citrullinated) vinculin, present in the joints of ACPA(+) RA patients, as an autoantigen targeted by ACPA and CD4(+) T cells. These T cells recognize an epitope with the core sequence DERAA, which is also found in many microbes and in protective HLA-DRB1*13 molecules, presented by predisposing HLA-DQ molecules. Moreover, these T cells crossreact with vinculin-derived and microbial-derived DERAA epitopes. Intriguingly, DERAA-directed T cells are not detected in HLA-DRB1*13(+) donors, indicating that the DERAA epitope from HLA-DRB1*13 mediates (thymic) tolerance in these donors and explaining the protective effects associated with HLA-DRB1*13. Together our data indicate the involvement of pathogen-induced DERAA-directed T cells in the HLA-RA association and provide a molecular basis for the contribution of protective/predisposing HLA alleles.
Background and Purpose
Calcitonin gene‐related peptide (CGRP) is a potent vasodilator. While its signalling is assumed to be mediated via increases in cAMP, this study focused on elucidating the ...actual intracellular signalling pathways involved in CGRP‐induced relaxation of human isolated coronary arteries (HCA).
Experimental Approach
HCA were obtained from heart valve donors (27 M, 25 F, age 54 ± 2 years). Concentration–response curves to human α‐CGRP or forskolin were constructed in HCA segments, incubated with different inhibitors of intracellular signalling pathways, and intracellular cAMP levels were measured with and without stimulation.
Results
Adenylyl cyclase (AC) inhibitors SQ22536 + DDA and MDL‐12330A, and PKA inhibitors Rp‐8‐Br‐cAMPs and H89, did not inhibit CGRP‐induced relaxation of HCA, nor did the guanylyl cyclase inhibitor ODQ, PKG inhibitor KT5823, EPAC1/2 inhibitor ESI09, potassium channel blockers TRAM‐34 + apamin, iberiotoxin or glibenclamide, or the Gαq inhibitor YM‐254890. Phosphodiesterase inhibitors induced a concentration‐dependent decrease in the response to KCl but did not potentiate relaxation to CGRP. Relaxation to forskolin was not blocked by PKA or AC inhibitors, although AC inhibitors significantly inhibited the increase in cAMP. Inhibition of Gβγ subunits using gallein significantly inhibited the relaxation to CGRP in human coronary arteries.
Conclusion
While CGRP signalling is generally assumed to act via cAMP, the CGRP‐induced vasodilation in HCA was not inhibited by targeting this intracellular signalling pathway at different levels. Instead, inhibition of Gβγ subunits did inhibit the relaxation to CGRP, suggesting a different mechanism of CGRP‐induced relaxation than generally believed.
Small interfering RNAs (siRNAs) targeting hepatic angiotensinogen (Agt) may provide long-lasting antihypertensive effects, but the optimal approach remains unclear. Here, we assessed the efficacy of ...a novel AGT siRNA in spontaneously hypertensive rats. Rats were treated with vehicle, siRNA (10 mg/kg fortnightly; subcutaneous), valsartan (31 mg/kg per day; oral), captopril (100 mg/kg per day; oral), valsartan+siRNA, or captopril+valsartan for 4 weeks (all groups, n=8). Mean arterial pressure (recorded via radiotelemetry) was lowered the most by valsartan+siRNA (−68±4 mm Hg), followed by captopril+valsartan (−54±4 mm Hg), captopril (−23±2 mm Hg), siRNA (−14±2 mm Hg), and valsartan (−10±2 mm Hg). siRNA and captopril monotherapies improved cardiac hypertrophy equally, but less than the dual therapies, which also lowered NT-proBNP (N-terminal pro-B-type natriuretic peptide). Glomerular filtration rate, urinary NGAL (neutrophil gelatinase-associated lipocalin), and albuminuria were unaffected by treatment. siRNA lowered circulating AGT by 97.9±1.0%, and by 99.8±0.1% in combination with valsartan. Although siRNA greatly reduced renal Ang (angiotensin) I, only valsartan+siRNA suppressed circulating and renal Ang II. This coincided with decreased renal sodium hydrogen exchanger type 3 and phosphorylated sodium chloride cotransporter abundances. Renin and plasma K increased with every treatment, but especially during valsartan+siRNA; no effects on aldosterone were observed. Collectively, these data indicate that Ang II elimination requires >99% suppression of circulating AGT. Maximal blockade of the renin-angiotensin system, achieved by valsartan+siRNA, yielded the greatest reduction in blood pressure and cardiac hypertrophy, whereas AGT lowering alone was as effective as conventional renin-angiotensin system inhibitors. Given its stable and sustained efficacy, lasting weeks, RNA interference may offer a unique approach to improving therapy adherence and treating hypertension.
PURPOSE OF REVIEWTo review recent progress in the genetics of rheumatoid arthritis (RA) and discuss the implications for understanding the pathogenesis of the disease as well as clinical application.
...RECENT FINDINGSProtection against anticitrullinated protein antibody (ACPA) positive RA was shown to be associated wit DRB1*1301. Genome-wide association studies (GWASs) added about 10 new loci to the list of already more than 20 loci associated with RA, so the list is now over 30. Typing for the known risk loci is not helpful for prediction of the risk for RA. It is remarkable how few functional studies have been published.
SUMMARYKnown genetic factors explain 50–60% of the genetic variance for susceptibility to ACPA-positive and 30–50% for ACPA-negative RA. Searching for the remaining missing or hidden heritability is in all probability not going to yield much for prediction and/or targeted intervention. Therefore, I conclude that if you want to find more genes you should have a lot of patience, time and money, stop with convential GWAS and invest in large-scale sequencing of selected patients and controls. I have a better suggestion, howeveruse the information that is already available to perform functional studies in order to understand the mechanism of the known associations!
Objective: We pharmacologically characterized pituitary adenylate cyclase–activating polypeptides (PACAPs), vasoactive intestinal peptide (VIP) and the VPAC1, VPAC2 and PAC1 receptors in human ...meningeal (for their role in migraine) and coronary (for potential side effects) arteries.
Methods: Concentration response curves to PACAP38, PACAP27, VIP and the VPAC1 receptor agonist (Lys15,Arg16,Leu27-VIP1-7-GRF8-27) were constructed in the absence or presence of the PAC1 receptor antagonist PACAP6-38 or the VPAC1 receptor antagonist, PG97269. mRNA expression was measured using qPCR.
Results: PACAP38 was less potent than VIP in both arteries. Both peptides had lower potency and efficacy in meningeal than in coronary arteries, while mRNA expression of VPAC1 receptor was more pronounced in meningeal arteries. PACAP6-38 reduced the Emax of PACAP27, while PG97269 right-shifted the VIP-induced relaxation curve only in the coronary arteries.
Conclusion: The direct vasodilatory effect of VIP and PACAP might be less relevant than the central effect of this compound in migraine pathogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Rheumatoid arthritis (RA) is a complex genetic disorder in which the HLA-region contributes most to the genetic risk. HLA-DRB1-molecules containing the amino acid sequence DERAA (i.e., HLA-DRB1*0103, ...*0402, *1102, *1103, *1301, *1302, and *1304) are associated with protection from RA. It has been proposed that not only inherited but also noninherited HLA-antigens from the mother (NIMA) can influence RA-susceptibility. Up to now, no protective NIMAs were described. Here, we studied whether DERAA-containing HLA-DRB1-alleles as NIMA are associated with a protective effect. One hundred seventy-nine families were studied, 88 from the Netherlands and 91 from the United Kingdom. The frequency of DERAA-containing HLA-DRB1-alleles of the Dutch mothers (16.1%), but not of the fathers (26.2%), was lower compared with the general Dutch population (29.3%; P = 0.02). This was replicated in the English set of patients and controls (P = 0.01). Further, of all families, 45 contained at least one DERAA-negative child with RA and at least one DERAA-positive parent. The odds for the DERAA-negative RA patients of having a DERAA-positive mother was significantly lower compared with having a DERAA-positive father (OR 0.25; P = 0.003). These data show a protective NIMA-effect in a human autoimmune disease and indicate that a DERAA-positive mother can transfer protection against RA to her DERAA-negative child.
Hemovigilance De Vries, René R.P; De Vries, René R.P; Faber, Jean-Claude
2012., 2012, 2012-07-11, 2012-07-17
eBook
* Hemovigilance is a "quality process" which aims to improve quality and increase safety of blood transfusion, by surveying all activities of the blood transfusion chain, from donors to recipients. ...Hemovigilance programmes have now been in existence for over 15 years, but many countries and centers are still at the development stage. This valuable resource brings together the main elements of such programmes and shows the different types of models available. A general introduction includes Chapters on hemovigilance as a quality tool for transfusion as well as concepts of and models for hemovigilance. The core of the book describes how Hemovigilance systems have been set up and how they work in hospitals, blood establishments, and at a national level. These Chapters are written according to a structured template: products and processes, documentation of jobs, monitoring and assessment, implementation and evaluation of measures for improvement, education and training. Chapters on Hemovigilance at the International level, Achievements and new developments complete the picture. Hemovigilance is above all a practical guide to setting up and improving hemovigilance systems, whilst raising awareness for reporting adverse events and reactions. This is the first international book on hemovigilance, assembling all the vital issues in one definitive reference source - essential reading for all staff involved in the transfusion process.
DNA damage is a causative factor in ageing of the vasculature and other organs. One of the most important vascular ageing features is reduced nitric oxide (NO)soluble guanylate cyclase (sGC)—cyclic ...guanosine monophosphate (cGMP) signaling. We hypothesized that the restoration of NO‐sGC‐cGMP signaling with an sGC activator (BAY 54–6544) may have beneficial effects on vascular ageing and premature death in DNA repair‐defective mice undergoing accelerated ageing. Eight weeks of treatment with a non‐pressor dosage of BAY 54–6544 restored the decreased in vivo microvascular cutaneous perfusion in progeroid Ercc1∆/− mice to the level of wild‐type mice. In addition, BAY 54–6544 increased survival of Ercc1∆/− mice. In isolated Ercc1∆/− aorta, the decreased endothelium‐independent vasodilation was restored after chronic BAY 54–6544 treatment. Senescence markers p16 and p21, and markers of inflammation, including Ccl2, Il6 in aorta and liver, and circulating IL‐6 and TNF‐α were increased in Ercc1∆/−, which was lowered by the treatment. Expression of antioxidant genes, including Cyb5r3 and Nqo1, was favorably changed by chronic BAY 54–6544 treatment. In summary, BAY 54–6544 treatment improved the vascular function and survival rates in mice with accelerated ageing, which may have implication in prolonging health span in progeria and normal ageing.
DNA repair deficiency in Ercc1∆/− mice cause a disruption of NO‐sGC‐cGMP signaling and a decrease of vasodilator response. These mice die prematurely between the age of 14 and 26 weeks and can be used to test interventions in ageing. Treatment with the BAY 54–6544 improved NO‐mediated vasodilation and attenuated vascular senescence and inflammation markers. Moreover, these changes are not restricted to vascular tissue, but manifest themselves also in liver, an organ that is often used to study changes in common ageing pathways in various models. Thus, BAY 54–6544 could be a potential therapeutic treatment to attenuate vascular ageing and improve survival.
Aging leads to a loss of vasomotor control. Both vasodilation and vasoconstriction are affected. Decreased nitric oxide-cGMP-mediated relaxation is a hallmark of aging. It contributes to vascular ...disease, notably hypertension, infarction, and dementia. Decreased vasodilation can be caused by aging independently from cardiovascular risk factors. This process that can be mimicked in mice in an accelerated way by activation of the DNA damage response. Genetic deletion of the DNA repair enzyme ERCC1 endonuclease in mice, as in the case of
mice, can be used as a tool to accelerate aging.
mice develop age-dependent vasomotor dysfunction from two months after birth. In the present study we tested if chronic treatment with sildenafil, a phosphodiesterase 5 inhibitor that augments NO-cGMP signaling, can reduce the development of vasomotor dysfunction in
mice.
mice and wild-type littermates were treated with 10 mg/kg/d of sildenafil from the age of 6 to the age of 14 weeks. Blood pressure and in vivo and ex vivo vasomotor responses were measured at the end of the treatment period.
mice developed decreased reactive hyperemia, and diminished NO-cGMP-dependent acetylcholine responses. The diminished acetylcholine response involved both endothelial and vascular smooth muscle cell signaling. Chronic sildenafil exclusively improved NO-cGMP signaling in VSMC, and had no effect on endothelium-derived hyperpolarization. Sildenafil also improved KCl hypocontractility in
mice. All effects were blood pressure-independent. The findings might be of clinical importance for prevention of morbidities related to vascular aging as well as for progeria patients with a high risk of cardiovascular disease.
PDF
