Méndez-Valdés Gabriel, Pérez-Carreño Vicente, Bragato Maria Chiara, Hundahl Malthe, Chichiarelli Silvia, Saso Luciano, Rodrigo Ramón
Molecular and Clinical Pharmacology Program, Faculty of Medicine, Campus Norte, Institute of Biomedical Sciences, University of Chile, Avda. Independencia 1027, Santiago 8380000, Chile.
Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Milan, Italy.
Biomedicines. 2022 Dec 22;11(1):17. doi: 10.3390/biomedicines11010017.
Ischemia/reperfusion injury is a process associated with cardiologic interventions, such as percutaneous coronary angioplasty after an acute myocardial infarction. Blood flow restoration causes a quick burst of reactive oxygen species (ROS), which generates multiple organelle damage, leading to the activation of cell death pathways. Therefore, the intervention contributes to a greater necrotic zone, thus increasing the risk of cardiovascular complications. A major cardiovascular ROS source in this setting is the activation of multiple NADPH oxidases, which could result via the occupancy of type 1 angiotensin II receptors (AT1R); hence, the renin angiotensin system (RAS) is associated with the generation of ROS during reperfusion. In addition, ROS can promote the expression of NF-κΒ, a proinflammatory transcription factor. Recent studies have described an intracellular RAS pathway that is associated with increased intramitochondrial ROS through the action of isoform NOX4 of NADPH oxidase, thereby contributing to mitochondrial dysfunction. On the other hand, the angiotensin II/ angiotensin type 2 receptor (Ang II/AT2R) axis exerts its effects by counter-modulating the action of AT1R, by activating endothelial nitric oxide synthase (eNOS) and stimulating cardioprotective pathways such as akt. The aim of this review is to discuss the possible use of AT1R blockers to hamper both the Ang II/AT1R axis and the associated ROS burst. Moreover; we suggest that AT1R antagonist drugs should act synergistically with other cardioprotective agents, such as ascorbic acid, N-acetylcysteine and deferoxamine, leading to an enhanced reduction in the reperfusion injury. This therapy is currently being tested in our laboratory and has shown promising outcomes in experimental studies.
缺血/再灌注损伤是一种与心脏介入治疗相关的过程，如急性心肌梗死后的经皮冠状动脉腔内血管成形术。血流恢复会引发活性氧（ROS）的快速爆发，这会导致多个细胞器受损，进而激活细胞死亡途径。因此，这种干预会导致更大的坏死区域，从而增加心血管并发症的风险。在这种情况下，主要的心血管ROS来源是多种NADPH氧化酶的激活，这可能是通过1型血管紧张素II受体（AT1R）的占据而产生的；因此，肾素血管紧张素系统（RAS）与再灌注期间ROS的产生有关。此外，ROS可促进促炎转录因子NF-κΒ的表达。最近的研究描述了一种细胞内RAS途径，该途径通过NADPH氧化酶的异构体NOX4的作用与线粒体内ROS的增加相关，从而导致线粒体功能障碍。另一方面，血管紧张素II/血管紧张素2型受体（Ang II/AT2R）轴通过对抗调节AT1R的作用、激活内皮型一氧化氮合酶（eNOS）和刺激诸如akt等心脏保护途径来发挥其作用。本综述的目的是讨论使用AT1R阻滞剂来阻碍Ang II/AT1R轴以及相关ROS爆发的可能性。此外，我们建议AT1R拮抗剂药物应与其他心脏保护剂如抗坏血酸、N-乙酰半胱氨酸和去铁胺协同作用，从而增强对再灌注损伤的减轻作用。这种疗法目前正在我们实验室进行测试，并且在实验研究中已显示出有希望的结果。
