Hyperoxia-induced KV channel regulation in an aging mouse model

摘要： 心血管疾病是美国和世界范围内的主要死亡原因。根据 根据美国心脏协会(AHA)的数据，平均每天报告的死亡人数超过2200人 每39秒增加1个。心律失常和心肌病在许多疾病中也有报道。 这些疾病包括急性肺损伤、糖尿病、肥胖、高血压和癌症。入院的病人 重症监护或重症监护病房(ICU)通常会出现高氧血症(PaO2&GT；100 用于治疗急性肺损伤、充血性心力衰竭、心脏纤维化。然而， 最近的研究表明，肺功能障碍和肺功能受损是 增加心脏的工作负荷，从而导致心脏重构，导致心律失常， 心力衰竭和死亡。在所有使用呼吸机的患者中，对#年死亡率的早期估计 机械通气率高达40%~45%。此外，现有报告表明，更多 住进ICU的人口中有50%以上是60岁以上的老年人。研究 还报告说，ICU中老年人口的住院死亡率显著高于年轻人 在机械通气持续时间方面没有差异的人群。这件事的确切性质是 问题仍然未知。在本研究中，我们将研究与心脏相关的基因。 高氧致衰老(老年)小鼠心脏重构和电重构的实验研究 分子、生化方法，并与幼龄成年小鼠比较。这些变化将 进一步研究它们在老年小鼠心脏发生生理变化中的作用 超声心动图、心电图和全细胞膜片钳技术，并将与 幼年成年小鼠。我们的初步数据还表明，将小鼠暴露在高氧中24小时 足以启动心脏重塑。因此，在这个提案中，我们将确定最优的 老年人高氧暴露时间及高氧引起的病理生理 老鼠的心脏是可以逆转的。我们还将研究心肌梗死的分子机制。 高氧条件下的重塑和电重塑，知道哪一个不仅重要 为了了解疾病的发展和进展，也为了开发有针对性的治疗 治愈疾病的方法。

Summary: Cardiovascular diseases are major cause of deaths in United States and Worldwide. According to American Heart Association (AHA), more than 2200 deaths reported every day with an average of 1 in every 39 seconds. Arrhythmias and cardiomyopathy is also reported in many diseased conditions including acute lung injury, diabetes, obesity, hypertension and cancer. Patients in critical care or intensive care unit (ICU) are often administered with hyperoxia (PaO2 > 100 mmHg) for treatment with acute lung injury, congestive heart failure, cardiac fibrosis. However, recent studies indicate that dysfunctional lung and compromised pulmonary functioning cause increased workload on the heart and therefore lead to cardiac remodeling resulting in arrhythmias, heart failure and death. Among all the ventilated patients, early estimates of mortality rates in mechanical ventilation was as high as 40-45%. Additionally, existing reports suggests that more than 50% of the population admitted to ICU are older adults with ages more than 60 years. Studies also reported significantly higher in-hospital mortality in older adult population in ICU than younger population without differences in the duration of mechanical ventilation. The exact nature of this problem remains unknown. In this study we will investigate the genes involved in ventricular remodeling and electrical remodeling in hyperoxia induced aged (older adult) mice hearts using molecular, and biochemical methods and compared with young adult mice. These changes will be further investigated for their roles in physiological changes occur in aged mice heart using echocardiography, ECG and whole-cell patch-clamping techniques and will be compared with young adult mice. Our preliminary data also suggests that exposure of mice to hyperoxia for 24h is enough to initiate cardiac remodeling. Therefore, in this proposal we will identify the optimum time of exposure for hyperoxia at which most of the pathophysiology induced by hyperoxia in aged mice hearts can be reversed. We will also investigate the molecular mechanisms of ventricular remodeling and electrical remodeling in hyperoxia conditions, knowing which not only important to understand the disease development and progression, but also to develop targeted therapy for the disease cure.