Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States.
Am J Physiol Heart Circ Physiol. 2024 Oct 1;327(4):H723-H732. doi: 10.1152/ajpheart.00265.2024. Epub 2024 Aug 9.
plays essential roles in the heart, where it encodes β-subunits that serve as modifiers of gene expression, cell surface channel activity, and cardiac conductivity. Reduced β function is linked to electrical instability in various diseases with cardiac manifestations and increased susceptibility to arrhythmias. Recently, we demonstrated that loss of in mice leads to compromised mitochondria energetics and reactive oxygen species (ROS) production. In this study, we examined the link between increased ROS and arrhythmia susceptibility in mice. In addition, ROS-scavenging capacity can be overwhelmed during prolonged oxidative stress, increasing arrhythmia susceptibility. Therefore, we isolated whole hearts and cardiomyocytes from and mice and subjected them to an oxidative challenge with diamide, a glutathione oxidant. Next, we analyzed gene expression and activity of antioxidant enzymes in hearts. Cells isolated from hearts died faster and displayed higher rates of ROS accumulation preceding cell death compared with those from . Furthermore, hearts showed higher arrhythmia scores and spent less time free of arrhythmia. Lastly, we found that protein expression and enzymatic activity of glutathione peroxidase is increased in hearts compared with wild type. Our results indicate that mice have decreased capability to manage ROS during prolonged oxidative stress. ROS accumulation is elevated and appears to overwhelm ROS scavenging through the glutathione system. This imbalance creates the potential for altered cell energetics that may underlie increased susceptibility to arrhythmias or other adverse cardiac outcomes. Using an oxidative challenge, we demonstrated that isolated cells from mice are more susceptible to cell death and surges in reactive oxygen species accumulation. At the whole organ level, they were also more susceptible to the formation of cardiac arrhythmias. This may in part be due to changes to the glutathione antioxidant system.
在心脏中发挥着重要作用，它编码β亚基，作为基因表达、细胞表面通道活性和心脏传导性的调节剂。β功能降低与各种有心脏表现的疾病中的电不稳定性有关，并且增加了心律失常的易感性。最近，我们证明了在小鼠中缺失 会导致线粒体能量代谢受损和活性氧（ROS）产生增加。在这项研究中，我们研究了 小鼠中 ROS 增加与心律失常易感性之间的联系。此外，在长时间氧化应激下，ROS 清除能力可能会被超过，从而增加心律失常的易感性。因此，我们从 和 小鼠中分离出心脏和心肌细胞，并使其受到谷胱甘肽氧化剂二酰胺的氧化应激。接下来，我们分析了 心脏中的抗氧化酶基因表达和活性。与 细胞相比，来自 心脏的细胞在细胞死亡之前更快地死亡并且显示出更高的 ROS 积累率。此外， 心脏表现出更高的心律失常评分并且没有心律失常的时间更短。最后，我们发现与野生型相比， 心脏中的谷胱甘肽过氧化物酶的蛋白表达和酶活性增加。我们的结果表明，在长时间氧化应激期间， 小鼠管理 ROS 的能力降低。ROS 积累增加，并且似乎通过谷胱甘肽系统超过了 ROS 清除。这种不平衡产生了改变细胞能量代谢的潜力，这可能是增加心律失常易感性或其他不良心脏结局的基础。通过氧化应激挑战，我们证明了来自 小鼠的分离细胞对细胞死亡和活性氧（ROS）积累的激增更敏感。在整个器官水平上，它们对心脏心律失常的形成也更敏感。这部分可能是由于谷胱甘肽抗氧化系统的变化。
