Hou Shanshan, Yan Xin, Gao Xiang, Jockusch Steffen, Gibson K Michael, Shan Zhiying, Bi Lanrong
Department of Chemistry, Michigan Technological University, Houghton, Michigan 49931, United States.
Center of Photochemical Sciences, Bowling Green State University, Bowling Green, Ohio 43403, United States.
ACS Omega. 2024 Sep 13;9(38):39401-39418. doi: 10.1021/acsomega.4c02725. eCollection 2024 Sep 24.
Ischemia/reperfusion (I/R) injury leads to apoptosis and extensive cellular and mitochondrial damage, triggered by the early generation and subsequent accumulation of mitochondrial reactive oxygen species (mtROS). This condition not only contributes to the pathology of I/R injury itself but is also implicated in a variety of other diseases, especially within the cardiovascular domain. Addressing mitochondrial oxidative stress thus emerges as a critical therapeutic target. In this context, our study introduces an indole-peptide-tempo conjugate (IPTC), a compound designed with dual functionalities: antioxidative properties and the ability to modulate autophagy. Our findings reveal that IPTC effectively shields H9C2 cardiomyocytes against hypoxia/reoxygenation (H/R) damage, primarily through counteracting mtROS overproduction linked to impaired mitophagy and mitochondrial dysfunction. We propose that IPTC operates by simultaneously reducing mtROS levels and inducing mitophagy, highlighting its potential as a novel therapeutic strategy for mitigating mitochondrial oxidative damage and, by extension, easing I/R injury and potentially other related cardiovascular conditions.
缺血/再灌注（I/R）损伤会导致细胞凋亡以及广泛的细胞和线粒体损伤，这是由线粒体活性氧（mtROS）的早期产生和随后的积累所引发的。这种情况不仅促成了I/R损伤本身的病理过程，还与多种其他疾病有关，尤其是在心血管领域。因此，解决线粒体氧化应激成为一个关键的治疗靶点。在此背景下，我们的研究引入了一种吲哚-肽-四甲基哌啶氧化物共轭物（IPTC），一种具有双重功能的化合物：抗氧化特性和调节自噬的能力。我们的研究结果表明，IPTC能有效保护H9C2心肌细胞免受缺氧/复氧（H/R）损伤，主要是通过对抗与线粒体自噬受损和线粒体功能障碍相关的mtROS过度产生。我们提出，IPTC通过同时降低mtROS水平和诱导线粒体自噬来发挥作用，突出了其作为一种新型治疗策略的潜力，可减轻线粒体氧化损伤，进而缓解I/R损伤以及潜在的其他相关心血管疾病。
