α1A-Adrenergic receptor prevents cardiac ischemic damage through PKCδ/GLUT1/4-mediated glucose uptake.
α1A-Adrenergic receptor prevents cardiac ischemic damage through PKCδ/GLUT1/4-mediated glucose uptake.
复制标题
DOI：
10.3109/10799893.2015.1091475
复制
发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Perez DM
中科院分区：
文献类型：
--
作者：
Shi T;Papay RS;Perez DM
虽然α1-肾上腺素能受体（AR）以前已被证明可以限制缺血性心脏损伤，但其机制仍不清楚。大多数以前的研究利用低氧条件下，除了缺血缓冲液与葡萄糖不足，但我们发现了深刻的差异，如果这两个条件分开。我们评估了小鼠新生儿和成年心肌细胞和HL-1细胞在一系列测定评估缺血性损伤缺氧或低糖条件下。我们发现，α1-AR刺激可防止乳酸脱氢酶释放增加或膜联蛋白V+细胞凋亡的条件下，由于低葡萄糖浓度，而不是缺氧。α1-AR拮抗剂哌唑嗪或非选择性PKC抑制剂可阻断这种保护作用。α1-AR刺激增加3 H-脱氧葡萄糖摄取，葡萄糖转运蛋白1或4（GLUT 1或GLUT 4）抑制剂或针对PKCδ的siRNA可阻断3 H-脱氧葡萄糖摄取。GLUT 1/4抑制也阻断了α1-AR介导的细胞凋亡保护作用。PKC抑制剂rottlerin或针对PKCδ的siRNA阻断了α1-AR刺激的GLUT 1或GLUT 4质膜转位。α1-AR刺激以时间依赖性方式增加GLUT 1或GLUT 4的质膜浓度。过表达α1A-AR但不表达α1B-AR的转基因小鼠在成年心脏中显示葡萄糖摄取增加和GLUT 1和GLUT 4质膜易位增加，而α1A-AR但不表达α1B-AR的敲除小鼠显示葡萄糖摄取和GLUT易位降低。我们的研究结果表明，α1-AR激活是抗凋亡和保护心肌缺血期间，由于葡萄糖剥夺，而不是缺氧，通过增加葡萄糖摄取到心脏通过PKCδ介导的GLUT易位，可能是特定的α1A-AR亚型。
While α1-adrenergic receptors (ARs) have been previously shown to limit ischemic cardiac damage, the mechanisms remain unclear. Most previous studies utilized low oxygen conditions in addition to ischemic buffers with glucose deficiencies but we discovered profound differences if the two conditions are separated. We assessed both mouse neonatal and adult myocytes and HL-1 cells in a series of assays assessing ischemic damage under hypoxic or low glucose conditions. We found that α1-AR stimulation protected against increased lactate dehydrogenase release or annexin V+ apoptosis under conditions that were due to low glucose concentration, not to hypoxia. The α1-AR antagonist prazosin or nonselective PKC inhibitors blocked the protective effect. α1-AR stimulation increased 3H-deoxyglucose uptake that was blocked with either an inhibitor to glucose transporter 1 or 4 (GLUT1 or GLUT4) or siRNA against PKCδ. GLUT1/4 inhibition also blocked α1-AR-mediated protection from apoptosis. The PKC inhibitor rottlerin or siRNA against PKCδ blocked α1-AR stimulated GLUT1 or GLUT4 plasma membrane translocation. α1-AR stimulation increased plasma membrane concentration of either GLUT1 or GLUT4 in a time-dependent fashion. Transgenic mice over-expressing the α1A-AR but not α1B-AR mice displayed increased glucose uptake and increased GLUT1 and GLUT4 plasma membrane translocation in the adult heart while α1A-AR but not α1B-AR knockout mice displayed lowered glucose uptake and GLUT translocation. Our results suggest that α1-AR activation is anti-apoptotic and protective during cardiac ischemia due to glucose deprivation and not hypoxia by enhancing glucose uptake into the heart via PKCδ-mediated GLUT translocation that may be specific to the α1A-AR subtype.