Dietl Alexander, Maack Christoph
Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421, Homburg, Germany.
Curr Heart Fail Rep. 2017 Aug;14(4):338-349. doi: 10.1007/s11897-017-0347-7.
In highly prevalent cardiac diseases, new therapeutic approaches are needed. Since the first description of oxidative stress in heart failure, reactive oxygen species (ROS) have been considered as attractive drug targets. Though clinical trials evaluating antioxidant vitamins as ROS-scavenging agents yielded neutral results in patients at cardiovascular risk, the knowledge of ROS as pathophysiological factors has considerably advanced in the past few years and led to novel treatment approaches. Here, we review recent new insights and current strategies in targeting mitochondrial calcium handling and ROS in heart failure.
Mitochondria are an important ROS source, and more recently, drug development focused on targeting mitochondria (e.g. by SS-31 or MitoQ). Important advancement has also been made to decipher how the matching of energy supply and demand through calcium (Ca) handling impacts on mitochondrial ROS production and elimination. This opens novel opportunities to ameliorate mitochondrial dysfunction in heart failure by targeting cytosolic and mitochondrial ion transporters to improve this matching process. According to this approach, highly specific substances as the preclinical CGP-37157, as well as the clinically used ranolazine and empagliflozin, provide promising results on different levels of evidence. Furthermore, the understanding of redox signalling relays, resembled by catalyst-mediated protein oxidation, is about to change former paradigms of ROS signalling. Novel methods, as redox proteomics, allow to precisely analyse key regulatory thiol switches, which may induce adaptive or maladaptive signalling. Additionally, the generation of genetically encoded probes increased the spatial and temporal resolution of ROS imaging and opened a new methodological window to subtle, formerly obscured processes. These novel insights may broaden our understanding of why previous attempts to target oxidative stress have failed, and at the same time provide us with new targets for drug development.
在常见的心脏疾病中，需要新的治疗方法。自心力衰竭中首次描述氧化应激以来，活性氧（ROS）一直被视为有吸引力的药物靶点。尽管评估抗氧化维生素作为ROS清除剂的临床试验在心血管疾病风险患者中产生了中性结果，但在过去几年中，关于ROS作为病理生理因素的认识有了很大进展，并导致了新的治疗方法。在此，我们综述心力衰竭中靶向线粒体钙处理和ROS的最新见解和当前策略。
线粒体是重要的ROS来源，最近，药物开发聚焦于靶向线粒体（如通过SS-31或MitoQ）。在解读通过钙（Ca）处理实现能量供需匹配如何影响线粒体ROS产生和清除方面也取得了重要进展。这为通过靶向胞质和线粒体离子转运体改善这种匹配过程来改善心力衰竭中的线粒体功能障碍提供了新机会。根据这种方法，临床前的CGP-37157以及临床使用的雷诺嗪和恩格列净等高度特异性物质在不同证据水平上都取得了有前景的结果。此外，对类似于催化剂介导的蛋白质氧化的氧化还原信号转导中继的理解即将改变ROS信号转导的先前范式。氧化还原蛋白质组学等新方法能够精确分析关键的调节性硫醇开关，这些开关可能诱导适应性或适应不良信号。此外，基因编码探针的产生提高了ROS成像的空间和时间分辨率，并为以前模糊不清的微妙过程打开了新的方法窗口。这些新见解可能拓宽我们对先前靶向氧化应激尝试为何失败的理解，同时为我们提供新的药物开发靶点。
