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Cardioprotection by NO2-OA was tested via inhibition through covalent adduct formation at C521. NO2-OA limited infarction in wild type hearts before IR, but protection was absent in C521S sEH knock-in mice, confirming cysteine dependence. A screened electrophile, RLC14, showed potent sEH inhibition (IC50 6.8×10−9 M) and protected wild type, not knock-in, hearts during IR, with mass spectrometry confirming C521 adduction via a disulfide-containing inhibitor.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/a-novel-inhibitor-of-soluble-epoxide-hydrolase-that-adducts-c521-is-cardioprotective-abstract/445804/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/a-novel-inhibitor-of-soluble-epoxide-hydrolase-that-adducts-c521-is-cardioprotective-abstract/445804.png","ImageObject",300,407,{"name":92,"@type":93},"Aurelia","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-09","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"How does soluble epoxide hydrolase (sEH) relate to cardiovascular health?","Question",{"text":113,"@type":114},"sEH hydrolyzes epoxides such as EETs into diols (DHETs). Because EETs promote vasodilation and lower blood pressure, inhibiting sEH increases EET availability and supports blood-pressure regulation and cardiovascular protection.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"What evidence shows that NO2-OA cardioprotection depends on C521?",{"text":118,"@type":114},"In isolated wild type hearts, NO2-OA given before ischemia and reperfusion reduced infarction. This protection was absent in C521S sEH knock-in mice, demonstrating that the C521 cysteine is critical for the protective effect.",{"name":120,"@type":111,"acceptedAnswer":121},"What is RLC14 and how was its cardioprotective mechanism established?",{"text":122,"@type":114},"RLC14 is a screened electrophilic inhibitor of sEH with an IC50 of 6.8×10−9 M. It reduced myocardial sEH activity and produced a selective plasma EET/DHET shift in wild type mice, and mass spectrometry showed RLC14 covalently adducts C521 through a disulfide-containing electrophile.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},445804,1791122528,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":52,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},1099514068365,"https://ap-avatar.wpscdn.com/avatar/10000253d8d9f28188e?_k=1776742907772140068","Redox Biology 89 (2026) 103974  \nContents lists available at ScienceDirect  \nRedox Biology  \njournal [homepage:](homepage: www.elsevier.com/locate/redox)[ www.elsevier.com/locate/redox](homepage: www.elsevier.com/locate/redox)  \n| A novel inhibitor of soluble epoxide hydrolase that adducts C521 is cardioprotective\u003Cbr>Rebecca L. Charles a,* , Mariana Fernandez-Caggiano a, Olena Rudykb, Izaak Tyson-Hirst c, Mazdak Ehteramyan a, Christopher H. Switzer d, Roberto Buccafusca e, Vinothini Rajeeve c, Katiuscia Bianchi c, Valle Morales c, Andrew J. Finch c, Philip Eaton a,**\u003Cbr>a William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK\u003Cbr>b School of Cardiovascular and Metabolic Medicine & Sciences, King’s College London, London, UK c Barts Cancer Institute, John Vane Science Centre, Queen Mary University of London, London, UK d Department of Molecular and Cell Biology, University of Leicester, Leicester, UK\u003Cbr>e School of Biological and Chemical Sciences, Queen Mary University of London, London, UK |  |  |\n| --- | --- | --- |\n| A R T I C L E I N F O |  | A B S T R A C T |\n| Keywords:\u003Cbr>Soluble epoxide hydrolase Inhibitor\u003Cbr>Thiol Heart\u003Cbr>Ischemia and reperfusion |  | The lipid electrophile nitro-oleic acid (NO 2-OA) and inhibitors of soluble epoxide hydrolase (sEH) limit injury during myocardial ischemia and reperfusion (IR). We investigated if cardioprotection by NO2-OA was mediated by inhibitory adduction of this electrophile to C521 of the hydrolase. Indeed, administering NO2-OA to wild type (WT) isolated perfused hearts prior to IR limited infarction, but this protection was absent in C521S sEH knock-in (KI) mice - demonstrating the critical importance of this cysteine. To identify more potent and selective inhibitors, we screened a library of electrophiles for their ability to inhibit sEH. A compound, we termed RLC14, had an IC50 of 6.8x10 − 9 M and protected WT, but not KI, isolated hearts from infarction during IR. Systemic administration of RLC14 decreased myocardial sEH activity and increased plasma EET/DHET ratio selectively in WT mice, consistent with inhibition of the hydrolase. In line with these findings, RLC14 protected WT, but not KI, mice from in vivo coronary artery ligation IR-induced infarction. Mass spectrometry analyses showed the novel electrophilic inhibitor, RLC14, which contains a disulfide, adducts to C521 in sEH to mediate its effects. This study identifies RLC14 as a potent cardioprotective agent that limits IR injury through C521-dependent hydrolase inhibition. |\n\n1. Introduction  \nSoluble epoxide hydrolase (sEH) catalyses the hydrolysis of epoxides such as EETs (epoxyeicosatrienoic acids) to their corresponding diols (dihydroxyeicosatrienoic acids, DHETs). EETs cause vasodilation and reduce blood pressure (BP) in hypertensive animals [1–5]. Consequently, sEH inhibition increases EETs abundance with consequent vasodilation, highlighting its importance in blood pressure regulation, an important determinant of cardiovascular health and disease [6–13]. Inhibitors of sEH afford broad cardiovascular protection, including blockade of smooth muscle proliferation [14], reduction of atherosclerosis and hypertension [15–20], prevention and regression of hypertrophy and heart failure [21–23], as well as limiting cardiac fibrosis [24]. sEH inhibition also limits ischemic damage in the heart [25–30],  \nbrain and other organs [31,32]. Similarly, sEH-null mice are protected from cardiovascular pathologies [27] and genetic alterations that promote enhanced hydrolase activity are a risk factor for human heart failure [21].  \nWe showed sEH activity is inhibited by electrophilic lipids, such as 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) or nitro-oleic acid (NO 2-OA) [33–35]. These endogenous lipid electrophiles bind and covalently adduct within the C-terminal hydrolase domain, inhibiting its catalytic activity to provide post-translational regulation of sEH. They ","cbCaioksq8sOZPZb","https://ap.wps.com/l/cbCaioksq8sOZPZb","pdf",5163314,"English","# A novel inhibitor of soluble epoxide hydrolase that adducts C521 is cardioprotective\n## Introduction","[{\"question\":\"How does soluble epoxide hydrolase (sEH) relate to cardiovascular health?\",\"answer\":\"sEH hydrolyzes epoxides such as EETs into diols (DHETs). Because EETs promote vasodilation and lower blood pressure, inhibiting sEH increases EET availability and supports blood-pressure regulation and cardiovascular protection.\"},{\"question\":\"What evidence shows that NO2-OA cardioprotection depends on C521?\",\"answer\":\"In isolated wild type hearts, NO2-OA given before ischemia and reperfusion reduced infarction. This protection was absent in C521S sEH knock-in mice, demonstrating that the C521 cysteine is critical for the protective effect.\"},{\"question\":\"What is RLC14 and how was its cardioprotective mechanism established?\",\"answer\":\"RLC14 is a screened electrophilic inhibitor of sEH with an IC50 of 6.8×10−9 M. It reduced myocardial sEH activity and produced a selective plasma EET/DHET shift in wild type mice, and mass spectrometry showed RLC14 covalently adducts C521 through a disulfide-containing electrophile.\"}]","A novel inhibitor of soluble epoxide hydrolase that adducts C521 is cardioprotective - abstract | PDF",1790712762,25]