Li Qun, Ren Jun
Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071, USA.
Aging Cell. 2007 Dec;6(6):799-806. doi: 10.1111/j.1474-9726.2007.00343.x. Epub 2007 Oct 30.
A fall in circulating levels of cardiac survival factor insulin-like growth factor 1 (IGF-1) contributes to cardiac aging. To better understand the role of IGF-1 in cardiac aging, we examined the influence of cardiac IGF-1 overexpression on lifespan, cardiomyocyte intracellular Ca2+ homeostasis, protein damage, apoptosis and expression of pro- and anti-apoptotic proteins in young and old mice. Mouse survival rate was constructed by the Kaplan-Meier curve. Intracellular Ca2+ was evaluated by fura-2 fluorescence. Protein damage was determined by protein carbonyl formation. Apoptosis was assessed by caspase-8 expression, caspase-3 and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) assay. Pro- and anti-apoptotic proteins including Bax, p53, pp53, Bcl2, Omi/HtrA2, apoptosis repressor with caspase recruitment domain (ARC) and X-linked inhibitor of apoptosis protein (XIAP) were assessed by Western blot. Aging decreased plasma in IGF-1 levels, elevated myocyte resting intracellular Ca2+ levels, reduced electrically stimulated rise in intracellular Ca2+ and delayed intracellular Ca2+ decay associated with enhanced protein carbonyl formation, caspase-8 expression and caspase-3 activity in FVB mice, all of which with the exception of elevated resting intracellular Ca2+ were attenuated by IGF-1. Aging up-regulated expression of Bax, Bcl2 and ARC, down-regulated XIAP expression and did not affect p53, pp53 and Omi/HtrA2. The IGF-1 transgene attenuated or nullified aging-induced changes in Bax, Bcl2 and XIAP. Our data suggest a beneficial role for IGF-1 in aging-induced survival, cardiac intracellular Ca2+ homeostasis, protein damage and apoptosis possibly related to pro- and anti-apoptotic proteins.
心脏存活因子胰岛素样生长因子1（IGF-1）循环水平的下降会导致心脏衰老。为了更好地理解IGF-1在心脏衰老中的作用，我们研究了心脏IGF-1过表达对年轻和老年小鼠寿命、心肌细胞内Ca2+稳态、蛋白质损伤、细胞凋亡以及促凋亡和抗凋亡蛋白表达的影响。通过Kaplan-Meier曲线构建小鼠存活率。用fura-2荧光评估细胞内Ca2+。通过蛋白质羰基形成测定蛋白质损伤。通过caspase-8表达、caspase-3和TUNEL（末端脱氧核苷酸转移酶介导的dUTP缺口末端标记）测定评估细胞凋亡。通过蛋白质印迹法评估包括Bax、p53、pp53、Bcl2、Omi/HtrA2、含半胱天冬酶募集结构域的凋亡抑制因子（ARC）和X连锁凋亡抑制蛋白（XIAP）在内的促凋亡和抗凋亡蛋白。衰老降低了血浆中IGF-1水平，升高了心肌细胞静息细胞内Ca2+水平，降低了电刺激引起的细胞内Ca2+升高，并延迟了细胞内Ca2+衰减，同时FVB小鼠中蛋白质羰基形成、caspase-8表达和caspase-3活性增强，除了升高的静息细胞内Ca2+外，所有这些都被IGF-1减弱。衰老上调了Bax、Bcl2和ARC的表达，下调了XIAP的表达，并且不影响p53、pp53和Omi/HtrA2。IGF-1转基因减弱或消除了衰老诱导的Bax、Bcl2和XIAP的变化。我们的数据表明IGF-1在衰老诱导的存活、心脏细胞内Ca2+稳态、蛋白质损伤和细胞凋亡中具有有益作用，这可能与促凋亡和抗凋亡蛋白有关。
