Palácio Plínio Bezerra, de Freitas Soares Geovanna Carvalho, Facundo Heberty Tarso
Faculdade de Medicina, Universidade Federal do Cariri, Barbalha, CE, Brazil.
Faculdade de Medicina, Universidade Federal do Cariri, Barbalha, CE, Brazil.
Arch Biochem Biophys. 2025 Jul;769:110418. doi: 10.1016/j.abb.2025.110418. Epub 2025 Apr 8.
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-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 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.
尽管进行了大量研究，但仍没有明确的疗法来预防缺血/再灌注损伤。在再灌注过程中，线粒体活性氧（ROS）会导致细胞损伤。缺血预处理（IP）以短暂的缺血和再灌注周期为特征，可激活线粒体ATP敏感性钾通道（mitoKATP）并提供心脏保护作用。本研究的目的是探讨截短的格列本脲（缺少环己基脲部分 - IMP-A）对缺血预处理（IP）介导的心脏保护作用的影响。我们的研究表明，IMP-A（2 - 5 μM）不会抑制IP对离体大鼠心脏缺血/再灌注损伤的保护作用。在此背景下，IP处理的心脏（无论有无IMP-A）表现出心脏功能得以保留，表现为左心室舒张末压、最大和最小一阶导数以及心率 - 压力乘积稳定，同时缺血/再灌注损伤后的梗死面积减小。相反，格列本脲（2 μM - 一种特征明确的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（无论是否用IMP-A处理）分离的线粒体产生的线粒体ROS水平显著降低，并且对线粒体通透性转换孔（mPTP）开放继发的钙诱导肿胀敏感性较低。此外，IP处理的心脏（无论是否用IMP-A处理）保留了蛋白质巯基。格列本脲增加了线粒体ROS的产生，并对IP心脏中的mPTP和巯基保护产生负面影响。重要的是，IP处理的心脏（无论是否用IMP-A处理）中线粒体氧消耗得以保留，并且这种保留被格列本脲破坏，但未被IMP-A破坏。这些发现表明，格列本脲的环己基脲基团对于其阻断IP介导的心脏保护作用的能力至关重要，为开发新的治疗策略提供了有价值的见解。
