Nitric oxide : biology and chemistry最新文献

{"title":"In vivo testing of novel nitric oxide-releasing nanoparticles for alleviating heart failure using the zebrafish embryo model","authors":"Maram Hasan ,&nbsp;Hadeel T. Zedan ,&nbsp;Dana Al-Fakhroo ,&nbsp;Hend Elsayed Ibrahim ,&nbsp;Sumaya Ibrahim Abiib ,&nbsp;Ibrahim M. El-Sherbiny ,&nbsp;Huseyin C. Yalcin","doi":"10.1016/j.niox.2024.01.007","DOIUrl":"10.1016/j.niox.2024.01.007","url":null,"abstract":"<div><p>Heart failure (HF) is a multifactorial, heterogeneous systemic disease that is considered one of the leading causes of death and morbidity worldwide. It is well-known that endothelial dysfunction (ED) plays an important role in cardiac disease etiology. A reduction in the bioavailability of nitric oxide (NO) in the bloodstream leads to vasoconstriction and ED. Many studies indicated diminishment of peripheral arteries vasodilation that is mediated by the endothelium in the of patients with chronic HF. With the advancement of nanomedicine, nanotechnology can provide adequate solutions for delivering exogenous NO with the aid of nanoparticles (NPs) to treat ED. The properties of superparamagnetic iron oxide nanoparticles (SPIONs) enable both passive and active delivery of drugs. This prompted us to investigate the efficacy of our newly-developed hydrogel nanoparticles (NO-RPs) for the delivery and sustained release of NO gas to alleviate cardiac failure and inflammation in the heart failure zebrafish model. The hydrogel NO-RPs incorporate SPIONS and NO precursor. The sustainend release of NO in the NO-RPs (4200 s), overcomes the problem of the short half life of NO in vivo which is expected to ameliorate the reduced NO bioavailabilty, and its consequences in endothelial and cardiac dysfunction. Zebrafish embryos were used as the animal model in this study to determine the effect of SPIONs-loaded NO-RPs on the cardiovascular system. Cardiac failure was induced in 24hpf embryos by exposure to aristolochic acid (AA)(0.25, 0.5 μM) for 8 h, followed by the SPIONs-loaded NO-RPs (0.25, 0.5 mg/ml) for 48 h, experimental groups included: control group which is healthy non treated zebrafish embryos, AA injured zebrafish embryos (HF) model,and NO-RP treated HF zebrafish embryos. Survival rate was assessed at 72hpf. Cardiac function was also evaluated by analyzing cardiac parameters including heartbeat, major blood vessels primordial cardinal vein and dorsal aorta (PCV &amp;DA) diameter, blood flow velocity in PCV &amp; DA vessels, cardiac output, and PCV &amp; DA shear stresses. All cardiac parameters were analyzed with the aid of MicroZebraLab blood flow analysis software from Viewpoint. In addition, we studied the molecular effects of the developed NO-RPs on the mRNA expression of selected pro-inflammatory markers: IL-6, and Cox-2. Our findings demonstrated that the NO-RPs improved the survival rate in the heart failure zebrafish model and reversed heart failure by enhancing blood flow perfusion in Zebrafish embryos, significantly. In addition, RT-PCR results showed that the NO-RPs significantly reduced the expression of pro-inflammatory markers (lL-6&amp;COX-2) in the heart failure zebrafish model. Our study confirmed that the developed SPIONs-loaded NO-RPs are effective tool to alleviate cardiac failure and inflammation in the HF zebrafish model.</p></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"144 ","pages":"Pages 47-57"},"PeriodicalIF":3.9,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1089860324000156/pdfft?md5=2121609ca74cc1e086c91cf4ad55885b&pid=1-s2.0-S1089860324000156-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139670169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydrogen sulfide donors across time: From origins to cutting-edge applications","authors":"Yuanqin Zhao,&nbsp;Yanxia Wang,&nbsp;Qian Xu,&nbsp;Kun Zhou,&nbsp;Yiming Shen,&nbsp;Liyuan Guo,&nbsp;Huiting Liu,&nbsp;Zhong Ren,&nbsp;Zhisheng Jiang","doi":"10.1016/j.niox.2024.01.003","DOIUrl":"10.1016/j.niox.2024.01.003","url":null,"abstract":"<div><p><span><span>This review aims to analyze the developmental trajectory of hydrogen sulfide (H2S) donors over the past three decades and explore the historical background, research hotspots, and emerging trends in related fields from a temporal perspective. A total of 5092 literature articles on H2S donors were retrieved from the Web of Science Core Collection (WoSCC), encompassing 1303 journals, 20638 authors, 10992 institutions, and 459 countries and regions. Utilizing CiteSpace as a </span>bibliometric tool, historical features, evolving active topics, and emerging trends in the field of H2S donors were identified. Over the past 30 years, the field of H2S donors has remained in a prominent stage. This article discusses both inorganic and organic types of H2S donors, including NaHS and Na2S, GYY4137, AP39, and AP123, as well as briefly outlines research and applications of H2S donors in nanotechnology, advanced materials, composite materials, nanostructures, and optical properties. Mechanistically, the review outlines how H2S donors regulate cellular </span>signal transduction, anti-inflammatory responses, neuroprotection, and other pathways within the organism by modulating protein S-sulfhydration, antioxidant effects, and interactions with metal proteins. In terms of applications, the review summarizes the extensive use of H2S donors in biomedical research, encompassing cardiovascular, neurological, anti-inflammatory, and anti-cancer characteristics, as well as their potential applications in the treatment of metabolic diseases. Finally, challenges and limitations faced by H2S donor research are discussed, and potential future research directions are proposed.</p></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"144 ","pages":"Pages 29-39"},"PeriodicalIF":3.9,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139664167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydrogen sulfide (H2S) metabolism: Unraveling cellular regulation, disease implications, and therapeutic prospects for precision medicine","authors":"Tejasvi Pandey ,&nbsp;Vivek Pandey","doi":"10.1016/j.niox.2024.01.004","DOIUrl":"10.1016/j.niox.2024.01.004","url":null,"abstract":"<div><p><span>Hydrogen sulfide (H</span>₂S), traditionally recognized as a noxious gas with a pungent odor, has emerged as a fascinating metabolite originating from proteinaceous foods. This review provides a comprehensive examination of H₂<span>S regulatory metabolism in cell. Dysregulation of cellular processes plays a pivotal role in the pathogenesis of numerous diseases. Recent development explores the chemistry of biosynthesis and degradation of H</span>₂S in cells. The consequences of dysregulation causing diseases and the emerging role of hydrogen sulfide (H₂<span>S) modulation as a promising therapeutic platform has not been explored much. These disturbances can manifest as oxidative stress<span>, inflammation, and aberrant cellular signaling pathways, contributing to the development and progression of diseases such as cancer, cardiovascular disorders, neurodegenerative diseases, and diabetes. Hydrogen sulfide has gained recognition as a key player in cellular regulation. H</span></span>₂<span>S is involved in numerous physiological processes<span>, including vasodilation, inflammation control, and cytoprotection. Recent advances in research have focused on modulating H</span></span>₂S levels to restore cellular balance and mitigate disease progression. This approach involves both exogenous H₂S donors and inhibitors of H₂<span>S -producing enzymes. By harnessing the versatile properties of H</span>₂S, researchers and clinicians may develop innovative therapies that address the root causes of dysregulation-induced diseases. As our understanding of H₂S biology deepens, the potential for precision medicine approaches tailored to specific diseases becomes increasingly exciting, holding the promise of improved patient outcomes and a new era in therapeutics.</p></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"144 ","pages":"Pages 20-28"},"PeriodicalIF":3.9,"publicationDate":"2024-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139499825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harmonizing hydrogen sulfide and nitric oxide: A duo defending plants against salinity stress","authors":"Gaurav Sharma ,&nbsp;Nandni Sharma ,&nbsp;Puja Ohri","doi":"10.1016/j.niox.2024.01.002","DOIUrl":"10.1016/j.niox.2024.01.002","url":null,"abstract":"<div><p><span>In the face of escalating salinity stress challenges in agricultural systems, this review article delves into the harmonious partnership between hydrogen sulfide (H</span>₂<span>S) and nitric oxide (NO) as they collectively act as formidable defenders of plants. Once considered as harmful pollutants, H</span>₂<span><span><span>S and NO have emerged as pivotal gaseous signal molecules that profoundly influence various facets of plant life. Their roles span from enhancing seed germination to promoting overall growth and development. Moreover, these molecules play a crucial role in bolstering stress tolerance mechanisms and maintaining essential plant </span>homeostasis. This review navigates through the intricate </span>signaling pathways associated with H</span>₂S and NO, elucidating their synergistic effects in combating salinity stress. We explore their potential to enhance crop productivity, thereby ensuring food security in saline-affected regions. In an era marked by pressing environmental challenges, the manipulation of H₂S and NO presents promising avenues for sustainable agriculture, offering a beacon of hope for the future of global food production.</p></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"144 ","pages":"Pages 1-10"},"PeriodicalIF":3.9,"publicationDate":"2024-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139373179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Are salivary NO2− / NO2− and NO3− levels biomarkers for dental caries in children? Systematic review and meta-analysis","authors":"Beatriz Díaz-Fabregat ,&nbsp;Wilmer Ramírez-Carmona ,&nbsp;Mark Lloyd Cannon ,&nbsp;Douglas Roberto Monteiro ,&nbsp;Juliano Pelim Pessan ,&nbsp;Cristina Antoniali","doi":"10.1016/j.niox.2024.01.001","DOIUrl":"10.1016/j.niox.2024.01.001","url":null,"abstract":"<div><p>The literature is conflicting regarding salivary nitrite (NO₂⁻)/nitrite and nitrate (NO₂⁻ and NO₃⁻) levels in children affected by dental caries. For this reason, a systematic review to provide a consensus on the subject was propose, whose objective is to verify whether these molecules could be used as biomarkers in children with caries. A comprehensive search was performed on online database and eleven articles were included in the meta-analysis. The methodological quality of studies was assessed by Newcastle-Ottawa Scale recommended for case-control studies and by AXIS tool for cross-sectional studies. Grading of Recommendations Assessment, Development and Evaluation was used for the assessment of the certainty of the evidence for each outcome. The results showed lower NO₂⁻ levels in the group of children affected by dental caries (SMD = −2.18 [-3.24, −1.13], p &lt; 0.01). Age, saliva collection and methods of evaluation can impact the results. When evaluating the severity of the condition, an important variation was detected in relation to the different evaluation methods NO₂⁻/NO₂⁻ and NO₃⁻. In conclusion, based on the evidence presented, the results suggest that NO₂⁻ levels in saliva are a possible biomarker of dental caries. Results should be evaluated with caution due to the very low evidence from primary studies. Longitudinal studies are necessary to strengthen this hypothesis.</p></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"144 ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139373219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory effects of curcumin on nitric oxide signaling in the cardiovascular system","authors":"Sajad Abolfazli ,&nbsp;Parham Mortazavi ,&nbsp;Ali Kheirandish ,&nbsp;Alexandra E. Butler ,&nbsp;Tannaz Jamialahmadi ,&nbsp;Amirhossein Sahebkar","doi":"10.1016/j.niox.2023.12.003","DOIUrl":"10.1016/j.niox.2023.12.003","url":null,"abstract":"<div><p><span><span><span>The continuously rising prevalence of cardiovascular disease (CVD) globally substantially impacts the economic growth of developing countries. Indeed, one of the leading causes of death worldwide is unfavorable cardiovascular events. Reduced nitric oxide (NO) generation is the pathogenic foundation of endothelial dysfunction, which is regarded as the first stage in the development of a number of CVDs. Nitric oxide exerts an array of biological effects, including </span>vasodilation, the suppression of vascular smooth muscle </span>cell proliferation<span> and the functional control of cardiac cells. Numerous treatment strategies aim to increase NO synthesis or upregulate downstream NO signaling pathways. The major component of </span></span><span><em>Curcuma</em><em> longa</em></span><span>, curcumin, has long been utilized in traditional medicine to treat various illnesses, especially CVDs. Curcumin improves CV function as well as having important pleiotropic effects, such as anti-inflammatory and antioxidant, through its ability to increase the bioavailability of NO and to positively impact NO-related signaling pathways. In this review, we discuss the scientific literature relating to curcumin's positive effects on NO signaling and vascular endothelial function.</span></p></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"143 ","pages":"Pages 16-28"},"PeriodicalIF":3.9,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139018813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparing in vitro nitric oxide blood uptake to its pulmonary diffusing capacity","authors":"Colin Borland ,&nbsp;Ruhi Patel","doi":"10.1016/j.niox.2023.11.006","DOIUrl":"10.1016/j.niox.2023.11.006","url":null,"abstract":"<div><p>Whether endothelium derived Nitric Oxide (NO) uptake by the blood is limited by a boundary layer, the red cell membrane or its interior is the subject of continued debate. Whether lung uptake of NO in the single-breath D_LNO test is limited by blood or not is also debated. To understand which processes are limiting blood NO uptake we have modelled NO chemical kinetics and we have derived a shrinking core model, Thiele Modulus and FTCS (Euler) numerical solution. In a rapid reaction apparatus, NO uptake appears limited by a boundary layer, and throughout the red cell, by diffusion. In the single breath situation, and arguably with endogenous NO <em>in vivo</em>, NO uptake appears limited by a boundary layer and a pseudo first order chemical reaction in the outer molecular layers of the red cell. We have not found evidence to support red cell membrane limitation.</p></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"143 ","pages":"Pages 29-43"},"PeriodicalIF":3.9,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1089860323001040/pdfft?md5=a44a334a6208d728173140ea30bba3da&pid=1-s2.0-S1089860323001040-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138885558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The pivotal role of neuronal nitric oxide synthase in the release of 6-nitrodopamine from mouse isolated vas deferens","authors":"José Britto-Júnior ,&nbsp;Samuel Goulart Nacário Silva ,&nbsp;Antonio Tiago Lima ,&nbsp;Vivian Fuguhara ,&nbsp;Larissa Bueno Andrade ,&nbsp;Gustavo Duarte Mendes ,&nbsp;Larryn W. Peterson ,&nbsp;Silvana Chiavegatto ,&nbsp;Edson Antunes ,&nbsp;Gilberto De Nucci","doi":"10.1016/j.niox.2023.12.002","DOIUrl":"10.1016/j.niox.2023.12.002","url":null,"abstract":"<div><p><span>6-Nitrodopamine (6-ND) is released from rat and human vas deferens and is considered a major mediator of both tissues contractility. The contractions induced by 6-ND are selectively blocked by both tricyclic antidepressants and α</span>₁<span>-adrenoceptor antagonists. Endothelial nitric oxide synthase (eNOS) is the major isoform responsible for 6-ND release in mouse isolated heart, however the origin of 6-ND in the vas deferens is unknown. Here it was investigated by LC-MS/MS the basal release of 6-ND from isolated vas deferens obtained from control, eNOS</span>^−/−<span>, nNOS</span>^−/−, and iNOS^−/− mice. In addition, it was evaluated <em>in vitro</em> vas deferens contractility following electric field stimulation (EFS).</p><p>Basal release of 6-ND was significantly reduced in nNOS^−/− mice compared to control mice, but not decreased when the vas deferens were obtained from either eNOS^−/− or iNOS^−/−<span> mice. Pre-incubation of the vas deferens with tetrodotoxin (1 μM) significantly reduced the basal release of 6-ND from control, eNOS</span>^−/−, and iNOS^−/− mice but had no effect on the basal release of 6-ND from nNOS^−/− mice. EFS-induced frequency-dependent contractions of the vas deferens, which were significantly reduced when the tissues obtained from control, eNOS^−/− and iNOS^−/− mice, were pre-incubated with <span>l</span>-NAME, but unaltered when the vas deferens was obtained from nNOS^−/− mice. In addition, the EFS-induced contractions were significantly smaller when the vas deferens were obtained from nNOS^−/− mice.</p><p>The results clearly demonstrate that nNOS is the main NO isoform responsible for 6-ND release in mouse vas deferens and reinforces the concept of 6-ND as a major modulator of vas deferens contractility.</p></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"143 ","pages":"Pages 1-8"},"PeriodicalIF":3.9,"publicationDate":"2023-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138581196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel pyridyl-substituted nitronyl nitroxides as potential antiarrhythmic and hypotensive agents with low toxicity and enhanced stability in aqueous solutions","authors":"Andrey E. Kolesnikov ,&nbsp;Arkadiy O. Bryzgalov ,&nbsp;Svyatoslav E. Tolstikov ,&nbsp;Vadim V. Yanshole ,&nbsp;Galina V. Romanenko ,&nbsp;Gleb A. Letyagin ,&nbsp;Kristina A. Smirnova ,&nbsp;Tatiana G. Tolstikova ,&nbsp;Artem S. Bogomyakov ,&nbsp;Victor I. Ovcharenko","doi":"10.1016/j.niox.2023.12.001","DOIUrl":"10.1016/j.niox.2023.12.001","url":null,"abstract":"<div><p><span>This study explores the antiarrhythmic and hypotensive potential of pyridyl-substituted nitronyl nitroxides derivatives, uncovering the crucial role of a single carbon moiety of the pyridine cycle alongside radical and charged oxygen centers of the imidazoline fragment. Notably, the introduction of fluorine atoms diminished the antiarrhythmic effect, while the most potent derivatives featured the nitronyl nitroxide pattern positioned at the third site of the pyridine cycle. Gender-dependent responses were observed in lead compounds L</span>^CF³ and L^Me, with L^Me inducing temporary bradycardia and hypotension specifically in female rats, and L^CF3 causing significant blood pressure reduction followed by rebound in females compared to milder effects in males. Mechanistic insights point towards β₁<span> adrenoceptor blockade as an underlying mechanism, supported by experiments on isolated rat atria. This research underscores the interplay between structure, cardiovascular effects and gender-specific responses, offering insights for therapeutic strategies for treating free radical-associated cardiovascular disorders.</span></p></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"143 ","pages":"Pages 9-15"},"PeriodicalIF":3.9,"publicationDate":"2023-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138685617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simvastatin restores pulmonary endothelial function in the setting of pulmonary over-circulation","authors":"Jason T. Boehme ,&nbsp;Xutong Sun ,&nbsp;Qing Lu ,&nbsp;Jubilee Barton ,&nbsp;Xiaomin Wu ,&nbsp;Wenhui Gong ,&nbsp;Gary W. Raff ,&nbsp;Sanjeev A. Datar ,&nbsp;Ting Wang ,&nbsp;Jeffrey R. Fineman ,&nbsp;Stephen M. Black","doi":"10.1016/j.niox.2023.11.007","DOIUrl":"10.1016/j.niox.2023.11.007","url":null,"abstract":"<div><p>Statin therapy is a cornerstone in the treatment of systemic vascular diseases. However, statins have failed to translate as therapeutics for pulmonary vascular disease. Early pulmonary vascular disease in the setting of congenital heart disease (CHD) is characterized by endothelial dysfunction, which precedes the more advanced stages of vascular remodeling. These features make CHD an ideal cohort in which to re-evaluate the potential pulmonary vascular benefits of statins, with a focus on endothelial biology. However, it is critical that the full gamut of the pleiotropic effects of statins in the endothelium are uncovered. The purpose of this investigation was to evaluate the therapeutic potential of simvastatin for children with CHD and pulmonary over-circulation, and examine mechanisms of simvastatin action on the endothelium. Our data demonstrate that daily simvastatin treatment preserves endothelial function in our shunt lamb model of pulmonary over-circulation. Further, using pulmonary arterial endothelial cells (PAECs) isolated from Shunt and control lambs, we identified a new mechanism of statin action mediated by increased expression of the endogenous Akt1 inhibitor, C-terminal modifying protein (CTMP). Increases in CTMP were able to decrease the Akt1-mediated mitochondrial redistribution of endothelial nitric oxide synthase (eNOS) which correlated with increased enzymatic coupling, identified by increases in NO generation and decreases in NOS-derived superoxide. Together our data identify a new mechanism by which simvastatin enhances NO signaling in the pulmonary endothelium and identify CTMP as a potential therapeutic target to prevent the endothelial dysfunction that occurs in children born with CHD resulting in pulmonary over-circulation.</p></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"142 ","pages":"Pages 58-68"},"PeriodicalIF":3.9,"publicationDate":"2023-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1089860323001052/pdfft?md5=e93841f637fa8539cec9a5608714941b&pid=1-s2.0-S1089860323001052-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138507456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}