Jain Kanika, Suryakumar Geetha, Prasad Rajendra, Ganju Lilly
Cellular Biochemistry Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi 110054, India.
Int J Cardiol. 2013 Oct 12;168(5):4667-77. doi: 10.1016/j.ijcard.2013.07.180. Epub 2013 Jul 31.
Low oxygen availability in the high altitude milieu causes adverse physiological and pathological consequences to the cardiopulmonary system. A key role is played by proteins in maintaining optimal cardiac function under stress. Differential response to hypoxia may be linked to the susceptibility of proteins to free radical induced modifications. The present study was designed to understand the significance of protein oxidation and ER stress in the myocardial response to hostile environments.
Sprague-Dawley rats were exposed to simulated hypoxia equivalent to 223 mmHg pressure, screened on the basis of time taken for onset of a characteristic hyperventilatory response and categorized as susceptible (<10 min), normal (10-25 min) or tolerant (>25 min). Protein modifications and activity of cellular proteolytic enzymes were assayed in myocardial tissue extracts to identify alterations in protein homeostasis. To evaluate the ER stress response, expression of various ER marker chaperones was investigated.
Susceptible animals displayed a distinct increase in protein oxidation and intracellular thiol content. They showed higher expression of ER stress hallmarks, GRP78, PDI and ERO1α, and exhibited a greater activation of the proteasome and calpain proteolytic systems, associated with elevated oxidized proteins. While a marked upregulation in the prosurvival signaling cascade PI3K/Akt/mTOR was observed in tolerant animals, the expression of pro-apoptotic caspase-3 and CHOP remained unaltered.
Thus, higher susceptibility to hypoxia is linked to a disruption in the proteostasis and activation of the ER stress response. Enhanced tolerance to hostile environments may be contributed by better maintenance of protein folding homeostasis.
高海拔环境中氧气供应不足会给心肺系统带来不良的生理和病理后果。蛋白质在应激状态下维持心脏最佳功能方面发挥着关键作用。对缺氧的不同反应可能与蛋白质对自由基诱导修饰的敏感性有关。本研究旨在了解蛋白质氧化和内质网应激在心肌对恶劣环境反应中的意义。
将Sprague-Dawley大鼠暴露于相当于223 mmHg压力的模拟低氧环境中，根据出现特征性过度通气反应所需的时间进行筛选，并分为易感组（<10分钟）、正常组（10 - 25分钟）或耐受组（>25分钟）。测定心肌组织提取物中的蛋白质修饰和细胞内蛋白水解酶的活性，以确定蛋白质稳态的变化。为评估内质网应激反应，研究了各种内质网标记伴侣蛋白的表达。
易感动物的蛋白质氧化和细胞内巯基含量明显增加。它们显示出内质网应激标志物GRP78、PDI和ERO1α的表达更高，并且蛋白酶体和钙蛋白酶蛋白水解系统的激活程度更大，这与氧化蛋白质水平升高有关。虽然在耐受动物中观察到促生存信号级联PI3K/Akt/mTOR有明显上调，但促凋亡半胱天冬酶-3和CHOP的表达保持不变。
因此，对缺氧的更高易感性与蛋白质稳态的破坏和内质网应激反应的激活有关。对恶劣环境的耐受性增强可能得益于蛋白质折叠稳态的更好维持。
