CaMKII-dependent phosphorylation of cardiac ryanodine receptors regulates cell death in cardiac ischemia/reperfusion injury.
CaMKII-dependent phosphorylation of cardiac ryanodine receptors regulates cell death in cardiac ischemia/reperfusion injury.
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心脏ryanodine受体的CAMKII依赖性磷酸化调节心脏缺血/再灌注损伤中的细胞死亡。
DOI：
10.1016/j.yjmcc.2014.06.004
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发表时间：
2014-09
影响因子：
5
通讯作者：
Mattiazzi, Alicia
中科院分区：
文献类型：
--
作者：
Di Carlo, Mariano N.;Said, Matilde;Ling, Haiyun;Valverde, Carlos A.;De Giusti, Veronica C.;Sommese, Leandro;Palomeque, Julieta;Aiello, Ernesto A.;Skapura, Darlene G.;Rinaldi, Gustavo;Respress, Jonathan L.;Brown, Joan Heller;Wehrens, Xander H. T.;Salas, Margarita A.;Mattiazzi, Alicia
Ca 2 +-钙调蛋白激酶II（CaMKII）激活在心肌缺血/再灌注（I/R）中是有害的。此外，抑制肌浆网（SR）的CaMKII依赖性磷酸化可防止CaMKII诱导的I/R损伤。然而，在SR水平的CaMKII的下游目标，负责这种不利的影响，仍然不清楚。在本研究中，我们的目的是剖析的作用，在SR水平上，受磷蛋白（PLN）和ryanodine受体（RyR 2），CaMKII依赖性I/R损伤的CaMKII的两个主要底物。在小鼠心脏进行全球I/R（45/120分钟），磷酸化的主要CaMKII网站，S2814对心脏RyR 2和T17对PLN，显着增加，而PKA依赖的磷酸化RyR 2和PLN的发病再灌注没有改变。在局部心肌I/R（1/24小时）小鼠体内获得了类似的结果。敲入小鼠RyR 2（S2814 A）上的丝氨酸2814磷酸化位点失活，显著改善缺血后机械恢复，减少梗死面积和减少细胞凋亡。相反，敲入小鼠，其中RyR 2的CaMKII位点被组成性激活（S2814 D），显著增加梗死面积并加剧细胞凋亡。在S2814 A和S2814 D小鼠局部心肌缺血，梗死面积也分别减少和增加。在PLN敲除背景（PLNDM）中具有双突变体不可磷酸化PLN（S16 A/T17 A）的转基因小鼠也显示出显著增加的缺血后心脏损伤。这种效应不能归因于PKA依赖性PLN磷酸化，也不是由于这些小鼠中存在的增强的L型Ca 2+电流。我们的研究结果揭示了RyR 2上S2814位点的磷酸化在CaMKII依赖性I/R心脏损伤中的重要作用。相比之下，他们表明再灌注期间CaMKII依赖性的PLN磷酸化增加会对抗而不是促进I/R损伤。
Ca2+-Calmodulin kinase II (CaMKII) activation is deleterious in cardiac ischemia/reperfusion (I/R). Moreover, inhibition of CaMKII-dependent phosphorylations at the sarcoplasmic reticulum (SR) prevents CaMKII-induced I/R damage. However, the downstream targets of CaMKII at the SR level, responsible for this detrimental effect, remain unclear. In the present study we aimed to dissect the role of the two main substrates of CaMKII at the SR level, phospholamban (PLN) and ryanodine receptors (RyR2), in CaMKII-dependent I/R injury. In mouse hearts subjected to global I/R (45/120 min), phosphorylation of the primary CaMKII sites, S2814 on cardiac RyR2 and of T17 on PLN, significantly increased at the onset of reperfusion whereas PKA-dependent phosphorylation of RyR2 and PLN did not change. Similar results were obtained in vivo, in mice subjected to regional myocardial I/R (1/24 hrs). Knock-in mice with an inactivated serine 2814 phosphorylation site on RyR2 (S2814A), significantly improved post-ischemic mechanical recovery, reduced infarct size and decreased apoptosis. Conversely, knock-in mice, in which CaMKII site of RyR2 is constitutively activated (S2814D), significantly increased infarct size and exacerbated apoptosis. In S2814A and S2814D mice subjected to regional myocardial ischemia, infarct size was also decreased and increased respectively. Transgenic mice with double-mutant non-phosphorylatable PLN (S16A/T17A) in the PLN knockout background (PLNDM) also showed significantly increased post-ischemic cardiac damage. This effect cannot be attributed to PKA-dependent PLN phosphorylation and was not due to the enhanced L-type Ca2+ current, present in these mice. Our results reveal a major role for the phosphorylation of S2814 site on RyR2 in CaMKII-dependent I/R cardiac damage. In contrast, they showed that CaMKII-dependent increase in PLN phosphorylation during reperfusion opposes rather than contributes to I/R damage.
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影响因子：
37.8
作者：
Go AS;Mozaffarian D;Roger VL;Benjamin EJ;Berry JD;Blaha MJ;Dai S;Ford ES;Fox CS;Franco S;Fullerton HJ;Gillespie C;Hailpern SM;Heit JA;Howard VJ;Huffman MD;Judd SE;Kissela BM;Kittner SJ;Lackland DT;Lichtman JH;Lisabeth LD;Mackey RH;Magid DJ;Marcus GM;Marelli A;Matchar DB;McGuire DK;Mohler ER 3rd;Moy CS;Mussolino ME;Neumar RW;Nichol G;Pandey DK;Paynter NP;Reeves MJ;Sorlie PD;Stein J;Towfighi A;Turan TN;Virani SS;Wong ND;Woo D;Turner MB;American Heart Association Statistics Committee and Stroke Statistics Subcommittee
通讯作者：
American Heart Association Statistics Committee and Stroke Statistics Subcommittee
DOI：
10.1152/ajpheart.00209.2003
发表时间：
2003-09-01
影响因子：
4.8
作者：
Said, M;Vittone, L;Mattiazzi, A
通讯作者：
Mattiazzi, A
DOI：
10.1111/j.1749-6632.1978.tb41979.x
发表时间：
1978-04-28
影响因子：
5.2
作者：
Fabiato, A;Fabiato, F
通讯作者：
Fabiato, F
影响因子：
10.8
作者：
Valverde, Carlos A.;Mundina-Wellenmann, Cecilia;Mattiazzi, Alicia
通讯作者：
Mattiazzi, Alicia
钙 - 钙调蛋白依赖性蛋白激酶II（CAMKII）：负责早期再灌注心律不齐的主要信号。
影响因子：
5
作者：
Said M;Becerra R;Valverde CA;Kaetzel MA;Dedman JR;Mundiña-Weilenmann C;Wehrens XH;Vittone L;Mattiazzi A
通讯作者：
Mattiazzi A