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Miriam M. Cortese-Krott Gunter G. C. Kuhnle Alex Dyson Bernadette O. Fernandez Marian Grman Jenna F. DuMond Mark P. Barrow George McLeod Hidehiko Nakagawa Karol Ondrias Péter Nagy S. Bruce King Joseph E. Saavedra Larry K. Keefer Mervyn Singer Malte Kelm Anthony R. Butler Martin Feelisch 《Proceedings of the National Academy of Sciences of the United States of America》2015,112(34):E4651-E4660
Experimental evidence suggests that nitric oxide (NO) and hydrogen sulfide (H2S) signaling pathways are intimately intertwined, with mutual attenuation or potentiation of biological responses in the cardiovascular system and elsewhere. The chemical basis of this interaction is elusive. Moreover, polysulfides recently emerged as potential mediators of H2S/sulfide signaling, but their biosynthesis and relationship to NO remain enigmatic. We sought to characterize the nature, chemical biology, and bioactivity of key reaction products formed in the NO/sulfide system. At physiological pH, we find that NO and sulfide form a network of cascading chemical reactions that generate radical intermediates as well as anionic and uncharged solutes, with accumulation of three major products: nitrosopersulfide (SSNO−), polysulfides, and dinitrososulfite [N-nitrosohydroxylamine-N-sulfonate (SULFI/NO)], each with a distinct chemical biology and in vitro and in vivo bioactivity. SSNO− is resistant to thiols and cyanolysis, efficiently donates both sulfane sulfur and NO, and potently lowers blood pressure. Polysulfides are both intermediates and products of SSNO− synthesis/decomposition, and they also decrease blood pressure and enhance arterial compliance. SULFI/NO is a weak combined NO/nitroxyl donor that releases mainly N2O on decomposition; although it affects blood pressure only mildly, it markedly increases cardiac contractility, and formation of its precursor sulfite likely contributes to NO scavenging. Our results unveil an unexpectedly rich network of coupled chemical reactions between NO and H2S/sulfide, suggesting that the bioactivity of either transmitter is governed by concomitant formation of polysulfides and anionic S/N-hybrid species. This conceptual framework would seem to offer ample opportunities for the modulation of fundamental biological processes governed by redox switching and sulfur trafficking.Nitrogen and sulfur are essential for all known forms of life on Earth. Our planet’s earliest atmosphere is likely to have contained only traces of O2 but rather large amounts of hydrogen sulfide (H2S) (1). Indeed, sulfide may have supported life long before the emergence of O2 and NO (2, 3).* This notion is consistent with a number of observations: H2S is essential for efficient abiotic amino acid generation as evidenced by the recent reanalysis of samples of Stanley Miller’s original spark discharge experiments (4), sulfide is an efficient reductant in protometabolic reactions forming RNA, protein, and lipid precursors (5), and sulfide is both a bacterial and mitochondrial substrate (6), enabling even multicellular lifeforms to exist and reproduce under conditions of permanent anoxia (7). Thus, although eukaryotic cells may have originated from the symbiosis of sulfur-reducing and -oxidizing lifeforms within a self-contained sulfur redox metabolome (8), sulfide may have been essential even earlier by providing the basic building blocks of life.The chemical reactions of sulfur-centered nucleophiles with a range of nitrogen-containing species have been studied for different reasons and as independent processes for more than a century, and early reports indicated complex reaction mechanisms (9–13). The recent surge of interest in this chemistry in the biological community (13–15) was triggered by a growing appreciation that NO and sulfide exert similar and often interdependent biological actions within the cardiovascular system and elsewhere (NO/H2S “cross-talk”) (16, 17), resulting in mutual attenuation or potentiation of their responses. This cross-talk is possibly mediated by chemical interactions (18–20), but much of the older chemical work seems to have been forgotten. Recently, low concentrations of sulfide were shown to quench NO-mediated vascular responses through formation of an uncharacterized “nitrosothiol” (RSNO) (18–20), assumed to be thionitrous acid (HSNO) (13–15).A recent report of the detection by MS of the highly unstable HSNO at physiological pH (21) has attracted considerable attention from the biological community, because it could be an intermediate in the reaction of sulfide with RSNOs (22) and a precursor for NO, nitrosonium (NO+) equivalents, and nitroxyl (HNO). However, a key aspect of HSNO’s properties that seems to have been overlooked in these discussions is its mobile hydrogen, allowing facile 1,3 hydrogen shift and formation of four isomers with the same chemical equation (13)—a feature described in the seminal studies by Goehring in the 1950s (23) and by Müller and Nonella later on (24, 25) that distinguishes HSNO from all other RSNOs (26). The same feature also contributes to the short half-life of the molecule at ambient temperatures, making it more probable that other yet unknown entities are involved as biological mediators of the NO/H2S cross-talk. Chemical studies by Seel and Wagner (9, 10) showed that NO readily reacts with HS− in basic aqueous solution or organic solvents under anoxic conditions to form the yellow nitrosopersulfide (SSNO−). Accumulation of this product was also observed after reaction of RSNOs with sulfide at pH 7.4 (26, 27); moreover, SSNO−-containing mixtures were found to release NO, activate soluble guanylyl cyclase (sGC) (26), and relax vascular tissue (28), although a contribution of other reaction products to these effects cannot be excluded. Meanwhile, other sulfane sulfur molecules, including persulfides (RSSH) and polysulfides (RSSn− and HSn−), have come to the fore as potential mediators of sulfide’s biological effects (29–31), but little is known about their pathways of formation, prevalence in biological systems, and relationship with NO.In view of this confusion, we sought to carry out an integrative chemical/pharmacological investigation to study the chemical biology of the reaction of NO with sulfide more thoroughly and systematically identify potentially bioactive reaction products. We here report that the NO/H2S interaction leads to formation of at least three product classes with distinct in vivo bioactivity profiles: nitrosopersulfide (SSNO−), polysulfides (HSn−), and dinitrososulfite [ONN(OH)SO3− or N-nitrosohydroxylamine-N-sulfonate (SULFI/NO)]; all anions at physiological pH. Their formation is accompanied by both scavenging and release of NO and H2S and formation of nitrous oxide (N2O), nitroxyl (HNO), nitrite (NO2−), nitrate (NO3−), and various sulfoxy species. These results not only offer an intriguing explanation for the quenching and potentiating effects of sulfide on NO bioavailability but also, provide a novel framework for modulation of fundamental biological processes governed by redox switching and sulfur trafficking. This chemistry is likely to prevail wherever NO and sulfide are cogenerated. 相似文献
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Daniel Scheiber Verena Veulemans Patrick Horn Martijn L. Chatrou Sebastian A. Potthoff Malte Kelm Leon J. Schurgers Ralf Westenfeld 《Nutrients》2015,7(8):6991-7011
Cardiovascular calcification is prevalent in the aging population and in patients with chronic kidney disease (CKD) and diabetes mellitus, giving rise to substantial morbidity and mortality. Vitamin K-dependent matrix Gla-protein (MGP) is an important inhibitor of calcification. The aim of this study was to evaluate the impact of high-dose menaquinone-7 (MK-7) supplementation (100 µg/g diet) on the development of extraosseous calcification in a murine model. Calcification was induced by 5/6 nephrectomy combined with high phosphate diet in rats. Sham operated animals served as controls. Animals received high or low MK-7 diets for 12 weeks. We assessed vital parameters, serum chemistry, creatinine clearance, and cardiac function. CKD provoked increased aortic (1.3 fold; p < 0.05) and myocardial (2.4 fold; p < 0.05) calcification in line with increased alkaline phosphatase levels (2.2 fold; p < 0.01). MK-7 supplementation inhibited cardiovascular calcification and decreased aortic alkaline phosphatase tissue concentrations. Furthermore, MK-7 supplementation increased aortic MGP messenger ribonucleic acid (mRNA) expression (10-fold; p < 0.05). CKD-induced arterial hypertension with secondary myocardial hypertrophy and increased elastic fiber breaking points in the arterial tunica media did not change with MK-7 supplementation. Our results show that high-dose MK-7 supplementation inhibits the development of cardiovascular calcification. The protective effect of MK-7 may be related to the inhibition of secondary mineralization of damaged vascular structures. 相似文献
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Recent advances in the understanding of the role of nitric oxide in cardiovascular homeostasis 总被引:6,自引:0,他引:6
Nitric oxide synthases (NOS) are the enzymes responsible for nitric oxide (NO) generation. To date, 3 distinct NOS isoforms have been identified: neuronal NOS (NOS1), inducible NOS (NOS2), and endothelial NOS (NOS3). Biochemically, NOS consists of a flavin-containing reductase domain, a heme-containing oxygenase domain, and regulatory sites. NOS catalyse an overall 5-electron oxidation of one Nomega-atom of the guanidino group of L-arginine to form NO and L-citrulline. NO exerts a plethora of biological effects in the cardiovascular system. The basal formation of NO in mitochondria by a mitochondrial NOS seems to be one of the main regulators of cellular respiration, mitochondrial transmembrane potential, and transmembrane proton gradient. This review focuses on recent advances in the understanding of the role of enzyme and enzyme-independent NO formation, regulation of NO bioactivity, new aspects of NO on cardiac function and morphology, and the clinical impact and perspectives of these recent advances in our knowledge on NO-related pathways. 相似文献
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Priv.-Doz. Dr. med. Ralf Zahn C. W. Hamm S. Schneider U. Zeymer G. Richardt M. Kelm B. Levenson T. Bonzel U. Tebbe G. Sabin C. A. Nienaber Thomas Pfannebecker J. Senges 《Clinical research in cardiology》2007,96(8):548-556
BACKGROUND: Drugeluting coronary stents (DES) are increasingly used during percutaneous coronary interventions (PCI). Due to limited budgets in Germany, no special reimbursement has been given for their use and therefore they were mainly used in selected patients. METHODS: In order to determine the change in indications in patients treated with a Sirolimus-eluting stent (SES) in daily clinical practice between 2002 and 2005, we analysed data from a prospective multi-centre DES registry, the German Cypher Stent Registry. RESULTS: From April 2002 until September 2005, 11 507 patients at 132 hospitals, who received at least one SES during their PCI, were included. Between 2002 and 2005, the median age of patients increased from 63 years to 66 years (p for trend <0.0001), whereas the prevalence of prior coronary bypass surgery (p<0.0001) and prior PCI (p<0.001) significantly decreased. Initial presentation of patients was stable over time, with a small increase of patients treated for non-ST elevation myocardial infarction (p=0.05). We found a significant increase in the treatment of complex stenoses (p<0.0001) as well as an increase in the proportion of chronic total occlusions (p<0.01). There was a steady increase in the proportion of patients treated for de novo lesions (p<0.0001), which was accompanied by a relative decrease in the proportion of patients treated for in-stent restenosis (p<0.0001). Concerning interventional characteristics a significant increase in the length of SES implanted per lesion, the numbers of SES implanted per lesion as well as an increase of the proportion of patients treated for more than one stenosis during one intervention could be observed (all p<0.0001). There was a significant decrease in the use of glycoprotein II b/IIIa antagonists during the PCI (2002: 26.5 to 14.2% in 2005, p<0.0001). MACE rates until hospital discharge did not change significantly over time. CONCLUSIONS: Between 2002 and 2005 there were two trends in the use of SES: a) a significant increase in the use of SES for de novo lesions and b) a significant trend to use SES for longer lesions, smaller arteries, more complex lesions and more SES per lesion. In summary these findings indicate that still SES are mainly used in patients with lesions that are at high risk for restenosis. 相似文献
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Sascha Jörg Hopp Ulf Culemann Jens Kelm Tim Pohlemann Antonius Pizanis 《Archives of orthopaedic and trauma surgery》2013,133(7):1003-1009
Introduction
Various surgical treatment options have been described in athletes with degenerative osteitis pubis who fail to respond to conservative treatment modalities. Although adductor longus tendinopathy often represents an additional pain generator in chronic groin pain associated with osteitis pubis, this has not been acknowledged in the surgical literature, to our knowledge. We present the results of a novel surgical technique for combined degenerative lesions of the pubic symphysis joint and the adjacent adductor longus tendon in a series of athletes with osteitis pubis.Methods
During 2009 and 2010, five competitive non-professional soccer players with considerable groin and pubic pain were referred to our clinic, after conservative therapy over a period of at least 12 months had failed. According to our clinical protocol for patients with groin pain, physical examination, pelvic radiographs and arthrography of the pubic symphysis to detect microlesions of the adjacent adductor longus tendons were performed. The patients diagnosed with degenerative osteitis pubis and concomitant lesion of the adductor longus origin were indicated for surgery. Surgery consisted of resection of the degenerative soft and bone tissue and subsequent reattachment with suture anchors. With regard to stability of the symphysis pubis, a two-portal arthroscopic curettage of the degenerative fibrocartilaginous disc tissue was performed. The patients were followed prospectively at medium term with assessment of general pain level (VAS score) and sport activity with pain (NIPPS score) pre- and postoperatively.Results
All patients recovered to full activity sports after an average period of 14.4 weeks. VAS and NIPPS scores markedly improved and overall satisfaction with the postoperative result was high. One intraoperative bleeding occurred, needing revision surgery. None of the patients developed pubic instability due to pubic symphysis curettage in the sequel.Conclusions
This novel surgical technique combines successfully stability-preserving arthroscopic pubic symphysis curettage with adductor debridement and reattachment in well-selected cases of athletes suffering from degenerative osteitis pubis and concomitant adductor pathology, being refractory to conservative treatment. Diligent preoperative evaluation of the specific pathology will lead to successful outcome. 相似文献10.
A. El Saman S. Meier A. Sander A. Kelm I. Marzi H. Laurer 《European journal of trauma and emergency surgery》2013,39(5):455-460