{"title":"缺乏环己脲部分的格列本脲类似物不能阻断缺血预适应诱导的线粒体和心脏对缺血/再灌注损伤的保护","authors":"Plínio Bezerra Palácio, Geovanna Carvalho de Freitas Soares, Heberty Tarso Facundo","doi":"10.1016/j.abb.2025.110418","DOIUrl":null,"url":null,"abstract":"<div><div>Despite significant research, there are no definitive therapies to prevent ischemia/reperfusion injury. During reperfusion, mitochondrial reactive oxygen species (ROS) cause cell damage. Ischemic preconditioning (IP), characterized by brief cycles of ischemia and reperfusion, activates mitochondrial ATP-sensitive potassium channels (mitoKATP) and provides cardioprotection. The aim of the present study is to investigate the impact of a truncated glibenclamide (lacking the cyclohexylurea portion - IMP-A) in ischemic preconditioning (IP)-mediated cardioprotection. Our study shows that IMP-A (2–5 μM) does not inhibit the protective effects of IP against ischemia/reperfusion damage in isolated rat hearts. In this context, IP hearts (with or without IMP-A) exhibited preserved cardiac function, as indicated by stable left ventricular developed pressure, maximal and minimal first derivatives, and rate-pressure product, along with a reduced infarct size following ischemia/reperfusion injury. Conversely, glibenclamide (2 μM - a well-characterized mitoKATP inhibitor) abolished the protective effects of IP against ischemia/reperfusion damage. Mitochondria isolated from reperfused IP hearts (treated or not with IMP-A) produced significantly lower levels of mitochondrial ROS and had lower susceptibility to Ca<sup>2+</sup>-induced swelling secondary to mitochondrial permeability transition pore (mPTP) opening. Additionally, IP hearts (treated or not with IMP-A) had preserved protein sulfhydryls. Glibenclamide elevated mitochondrial ROS production and negatively impacted mPTP and the sulfhydryl protection seen in IP hearts. Importantly, mitochondrial O<sub>2</sub> consumption was preserved in IP hearts (treated or not with IMP-A), and this preservation was disrupted by glibenclamide but not by IMP-A. These findings suggest that the cyclohexylurea group of glibenclamide is essential for its ability to block IP-mediated cardioprotection, providing valuable insights for developing novel therapeutic strategies.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"769 ","pages":"Article 110418"},"PeriodicalIF":3.0000,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A glibenclamide analog lacking the cyclohexylurea portion fails to block ischemic preconditioning-induced mitochondrial and cardiac protection against ischemia/reperfusion injury\",\"authors\":\"Plínio Bezerra Palácio, Geovanna Carvalho de Freitas Soares, Heberty Tarso Facundo\",\"doi\":\"10.1016/j.abb.2025.110418\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Despite significant research, there are no definitive therapies to prevent ischemia/reperfusion injury. During reperfusion, mitochondrial reactive oxygen species (ROS) cause cell damage. Ischemic preconditioning (IP), characterized by brief cycles of ischemia and reperfusion, activates mitochondrial ATP-sensitive potassium channels (mitoKATP) and provides cardioprotection. The aim of the present study is to investigate the impact of a truncated glibenclamide (lacking the cyclohexylurea portion - IMP-A) in ischemic preconditioning (IP)-mediated cardioprotection. Our study shows that IMP-A (2–5 μM) does not inhibit the protective effects of IP against ischemia/reperfusion damage in isolated rat hearts. In this context, IP hearts (with or without IMP-A) exhibited preserved cardiac function, as indicated by stable left ventricular developed pressure, maximal and minimal first derivatives, and rate-pressure product, along with a reduced infarct size following ischemia/reperfusion injury. Conversely, glibenclamide (2 μM - a well-characterized mitoKATP inhibitor) abolished the protective effects of IP against ischemia/reperfusion damage. Mitochondria isolated from reperfused IP hearts (treated or not with IMP-A) produced significantly lower levels of mitochondrial ROS and had lower susceptibility to Ca<sup>2+</sup>-induced swelling secondary to mitochondrial permeability transition pore (mPTP) opening. Additionally, IP hearts (treated or not with IMP-A) had preserved protein sulfhydryls. Glibenclamide elevated mitochondrial ROS production and negatively impacted mPTP and the sulfhydryl protection seen in IP hearts. Importantly, mitochondrial O<sub>2</sub> consumption was preserved in IP hearts (treated or not with IMP-A), and this preservation was disrupted by glibenclamide but not by IMP-A. These findings suggest that the cyclohexylurea group of glibenclamide is essential for its ability to block IP-mediated cardioprotection, providing valuable insights for developing novel therapeutic strategies.</div></div>\",\"PeriodicalId\":8174,\"journal\":{\"name\":\"Archives of biochemistry and biophysics\",\"volume\":\"769 \",\"pages\":\"Article 110418\"},\"PeriodicalIF\":3.0000,\"publicationDate\":\"2025-04-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Archives of biochemistry and biophysics\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0003986125001316\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Archives of biochemistry and biophysics","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0003986125001316","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
A glibenclamide analog lacking the cyclohexylurea portion fails to block ischemic preconditioning-induced mitochondrial and cardiac protection against ischemia/reperfusion injury
Despite significant research, there are no definitive therapies to prevent ischemia/reperfusion injury. During reperfusion, mitochondrial reactive oxygen species (ROS) cause cell damage. Ischemic preconditioning (IP), characterized by brief cycles of ischemia and reperfusion, activates mitochondrial ATP-sensitive potassium channels (mitoKATP) and provides cardioprotection. The aim of the present study is to investigate the impact of a truncated glibenclamide (lacking the cyclohexylurea portion - IMP-A) in ischemic preconditioning (IP)-mediated cardioprotection. Our study shows that IMP-A (2–5 μM) does not inhibit the protective effects of IP against ischemia/reperfusion damage in isolated rat hearts. In this context, IP hearts (with or without IMP-A) exhibited preserved cardiac function, as indicated by stable left ventricular developed pressure, maximal and minimal first derivatives, and rate-pressure product, along with a reduced infarct size following ischemia/reperfusion injury. Conversely, glibenclamide (2 μM - a well-characterized mitoKATP inhibitor) abolished the protective effects of IP against ischemia/reperfusion damage. Mitochondria isolated from reperfused IP hearts (treated or not with IMP-A) produced significantly lower levels of mitochondrial ROS and had lower susceptibility to Ca2+-induced swelling secondary to mitochondrial permeability transition pore (mPTP) opening. Additionally, IP hearts (treated or not with IMP-A) had preserved protein sulfhydryls. Glibenclamide elevated mitochondrial ROS production and negatively impacted mPTP and the sulfhydryl protection seen in IP hearts. Importantly, mitochondrial O2 consumption was preserved in IP hearts (treated or not with IMP-A), and this preservation was disrupted by glibenclamide but not by IMP-A. These findings suggest that the cyclohexylurea group of glibenclamide is essential for its ability to block IP-mediated cardioprotection, providing valuable insights for developing novel therapeutic strategies.
期刊介绍:
Archives of Biochemistry and Biophysics publishes quality original articles and reviews in the developing areas of biochemistry and biophysics.
Research Areas Include:
• Enzyme and protein structure, function, regulation. Folding, turnover, and post-translational processing
• Biological oxidations, free radical reactions, redox signaling, oxygenases, P450 reactions
• Signal transduction, receptors, membrane transport, intracellular signals. Cellular and integrated metabolism.