Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda, MD, USA.
Front Cell Neurosci. 2014 Dec 4;8:416. doi: 10.3389/fncel.2014.00416. eCollection 2014.
The molecular mechanisms underlying hypothermic neuroprotection have yet to be fully elucidated. Herein we demonstrate that global SUMOylation, a form of post-translational modification with the Small Ubiquitin-like MOdifer, participates in the multimodal molecular induction of hypothermia-induced ischemic tolerance. Mild (32°C) to moderate (28°C) hypothermic treatment(s) during OGD (oxygen-glucose-deprivation) or ROG (restoration of oxygen/glucose) increased global SUMO-conjugation levels and protected cells (both SHSY5Y and E18 rat cortical neurons) from OGD and ROG-induced cell death. Hypothermic exposure either before or after permanent middle cerebral artery occlusion (pMCAO) surgery in wild type mice increased global SUMO-conjugation levels in the brain and in so doing protected these animals from pMCAO-induced ischemic damage. Of note, hypothermic exposure did not provide an additional increase in protection from pMCAO-induced ischemic brain damage in Ubc9 transgenic (Ubc9 Tg) mice, which overexpress the sole E2 SUMO conjugating enzyme and thereby display elevated basal levels of global SUMOylation under normothermic conditions. Such evidence suggests that increases in global SUMOylation are critical and may account for a substantial part of the observed increase in cellular tolerance to brain ischemia caused via hypothermia.
低温神经保护的分子机制尚未完全阐明。在此，我们证明了全身性 SUMO 化，一种带有小泛素样修饰物的翻译后修饰形式，参与了低温诱导的缺血耐受的多模式分子诱导。在 OGD（氧葡萄糖剥夺）或 ROG（氧/葡萄糖恢复）期间进行轻度（32°C）至中度（28°C）低温处理会增加全局 SUMO 缀合水平，并保护细胞（SHSY5Y 和 E18 大鼠皮质神经元）免受 OGD 和 ROG 诱导的细胞死亡。在野生型小鼠的永久性大脑中动脉闭塞（pMCAO）手术之前或之后进行低温暴露会增加大脑中的全局 SUMO 缀合水平，从而保护这些动物免受 pMCAO 诱导的缺血损伤。值得注意的是，低温暴露并未为 Ubc9 转基因（Ubc9 Tg）小鼠的 pMCAO 诱导的缺血性脑损伤提供额外的保护作用，Ubc9 Tg 小鼠过表达唯一的 E2 SUMO 缀合酶，因此在正常体温条件下表现出基础水平升高的全局 SUMO 化。这种证据表明，全局 SUMO 化的增加是至关重要的，可能是通过低温引起的细胞对脑缺血耐受性增加的主要原因之一。
