A glibenclamide analog lacking the cyclohexylurea portion fails to block ischemic preconditioning-induced mitochondrial and cardiac protection against ischemia/reperfusion injury

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics Pub Date : 2025-04-08 DOI:10.1016/j.abb.2025.110418

Plínio Bezerra Palácio, Geovanna Carvalho de Freitas Soares, Heberty Tarso Facundo

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Abstract

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.

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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

尽管有大量的研究，目前还没有明确的治疗方法来预防缺血/再灌注损伤。在再灌注过程中，线粒体活性氧（ROS）引起细胞损伤。缺血预处理（IP）以缺血和再灌注的短周期为特征，激活线粒体atp敏感钾通道（mitoKATP）并提供心脏保护。本研究的目的是研究截断格列本脲（缺乏环己脲部分- IMP-A）在缺血预处理（IP）介导的心脏保护中的影响。我们的研究表明，IMP-A （2-5 μM）不抑制IP对离体大鼠心脏缺血再灌注损伤的保护作用。在这种情况下，IP心脏（有或没有IMP-A）表现出保留的心功能，如稳定的左心室发育压，最大和最小一阶导数，心率压积，以及缺血/再灌注损伤后梗死面积的缩小。相反，格列本脲（2 μM -一种表征良好的mitoKATP抑制剂）消除了IP对缺血/再灌注损伤的保护作用。从再灌注的IP心脏中分离的线粒体（无论是否使用IMP-A处理）产生的线粒体ROS水平显著降低，并且对Ca2+诱导的线粒体通透性过渡孔（mPTP）打开引起的肿胀的易感性降低。此外，IP心脏（无论是否用IMP-A处理）都保留了蛋白质巯基。格列本脲提高线粒体ROS的产生，并对IP心脏的mPTP和巯基保护产生负面影响。重要的是，IP心脏（无论是否用IMP-A处理）的线粒体氧消耗被保留，这种保存被格列本脲破坏，而IMP-A没有。这些发现表明，格列本脲的环己脲基团对其阻断ip介导的心脏保护的能力至关重要，为开发新的治疗策略提供了有价值的见解。

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来源期刊

Archives of biochemistry and biophysics 生物-生化与分子生物学

CiteScore

7.40

自引率

0.00%

发文量

245

审稿时长

26 days

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.