Β-adrenergic receptor stimulation induces endoplasmic reticulum stress in adult cardiac myocytes: role in apoptosis.
Β-adrenergic receptor stimulation induces endoplasmic reticulum stress in adult cardiac myocytes: role in apoptosis.
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DOI：
10.1007/s11010-011-1205-7
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发表时间：
2012-05
影响因子：
4.3
通讯作者：
Singh, Krishna
中科院分区：
文献类型：
--
作者：
Dalal, Suman;Foster, Cerrone R.;Das, Bhudev C.;Singh, Mahipal;Singh, Krishna
错误折叠蛋白的积累和钙稳态的改变诱导内质网（ER）应激，导致细胞凋亡。在这里，我们测试了β-AR刺激诱导ER应激的假设，并且ER应激的诱导在心肌细胞中起促凋亡作用。使用毒胡萝卜素和布雷菲德菌素A，我们证明，ER应激诱导成年大鼠心室肌细胞（ARVMs）的凋亡。β-AR刺激（异丙肾上腺素; 3 h）显著增加了ARVM中ER应激蛋白（如GRP-78、Gadd-153和Gadd-34）的表达，同时激活了caspase-12。在大多数情况下，这些作用被毒胡萝卜素模仿。β-AR刺激15 min可增加PERK和eIF-2α的磷酸化。PERK磷酸化水平仍然较高，而eIF-2α磷酸化水平随后下降，在β-AR刺激后3 h达到低于基础水平的约50%。β1-AR而非β2-AR拮抗剂阻止了eIF-2α磷酸化的下降。腺苷酸环化酶激活剂Forskolin模拟ISO对eIF-2α磷酸化的影响。Salubrinal是一种ER应激抑制剂，可维持eIF-2α磷酸化并抑制β-AR刺激的细胞凋亡。此外，使用z-ATAD抑制caspase-12可抑制β-AR刺激和毒胡萝卜素诱导的细胞凋亡。在体内，β-AR刺激可诱导小鼠心脏中的ER应激，表现为GRP-78和Gadd-153表达增加、caspase-12活化和eIF-2α去磷酸化。Salubrinal维持eIF-2α的磷酸化，抑制caspase-12的活化，减少β-AR刺激的心脏细胞凋亡。因此，β-AR刺激诱导心肌细胞和心脏中的ER应激，并且ER应激的诱导起促凋亡作用。
Accumulation of misfolded proteins and alterations in calcium homeostasis induces endoplasmic reticulum (ER) stress, leading to apoptosis. Here we tested the hypothesis that β-AR stimulation induces ER stress, and induction of ER stress plays a pro-apoptotic role in cardiac myocytes. Using thapsigargin and brefeldin A, we demonstrate that ER stress induces apoptosis in adult rat ventricular myocytes (ARVMs). β-AR-stimulation (isoproterenol; 3h) significantly increased expression of ER stress proteins such as GRP-78, Gadd-153 and Gadd-34, while activating caspase-12 in ARVMs. In most parts, these effects were mimicked by thapsigargin. β-AR stimulation for 15 min increased PERK and eIF-2α phosphorylation. PERK phosphorylation remained higher, while eIF-2α phosphorylation declined thereafter, reaching to ~50% below basal levels 3 h after β-AR stimulation. This decline in eIF-2α phosphorylation was prevented by β1-AR, not by β2-AR, antagonist. Forskolin, adenylyl cyclase activator, simulated the effects of ISO on eIF-2α phosphorylation. Salubrinal, an ER stress inhibitor, maintained eIF-2α phosphorylation and inhibited β-AR-stimulated apoptosis. Furthermore, inhibition of caspase-12 using z-ATAD inhibited β-AR-stimulated and thapsigargin-induced apoptosis. In vivo, β-AR stimulation induced ER stress in the mouse heart as evidenced by increased expression of GRP-78 and Gadd-153, activation of caspase-12 and dephosphorylation of eIF-2α. Salubrinal maintained phosphorylation of eIF-2α, inhibited activation of caspase-12 and decreased β-AR-stimulated apoptosis in the heart. Thus β-AR stimulation induces ER stress in cardiac myocytes and in the heart, and induction of ER stress plays a pro-apoptotic role.
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DOI：
10.1074/jbc.m109.014092
发表时间：
2010-02-26
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Armstrong JL;Flockhart R;Veal GJ;Lovat PE;Redfern CP
通讯作者：
Redfern CP
影响因子：
11.4
作者：
Germain, M;Mathai, JP;Shore, GC
通讯作者：
Shore, GC
影响因子：
20.1
作者：
Remondino, A;Kwon, SH;Colucci, WS
通讯作者：
Colucci, WS
影响因子：
10.8
作者：
Nickson, Philip;Toth, Ambrus;Erhardt, Peter
通讯作者：
Erhardt, Peter
影响因子：
5.3
作者：
Hamada, H;Suzuki, M;Aoe, T
通讯作者：
Aoe, T