CaMKII Serine 280 O-GlcNAcylation Links Diabetic Hyperglycemia to Proarrhythmia.
CaMKII Serine 280 O-GlcNAcylation Links Diabetic Hyperglycemia to Proarrhythmia.
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DOI：
10.1161/circresaha.120.318402
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发表时间：
2021-06-25
影响因子：
20.1
通讯作者：
Bers DM
中科院分区：
文献类型：
--
作者：
Hegyi B;Fasoli A;Ko CY;Van BW;Alim CC;Shen EY;Ciccozzi MM;Tapa S;Ripplinger CM;Erickson JR;Bossuyt J;Bers DM
补充数字内容可在文本中找到。糖尿病性高血糖症与心功能障碍和心律失常风险增加相关，并且涉及CaMKII（钙/钙调蛋白依赖性蛋白激酶II）功能。已知CaMKII位点的氧化和O-连接的β-N-乙酰葡糖胺（O-GlcNAc）均促进CaMKII活性。研究人类糖尿病心脏中发生的翻译后修饰以及它们如何改变高血糖时的电生理和Ca 2+处理特性。我们评估了超声心动图，电生理学，Ca 2+处理，和蛋白质表达的位点特异性CaMKII突变小鼠（O-GlcNAc-抗性S280 A和抗氧化MM 281/2 VV基因敲入，和全球和心脏特异性基因敲除），在心肌细胞急性高血糖和血管紧张素II（血管紧张素II）和链脲佐菌素注射后的小鼠（诱导糖尿病）。患有糖尿病的人类患者表现出升高的CaMKII O-GlcNAc化，但不表现出氧化。在小鼠中，急性高血糖增加自发性舒张期Ca 2+火花和波以及致心律失常动作电位变化（延长、交替和延迟后去极化），所有这些都需要CaMKII-S280 O-GlcNAc化。Ang II的作用依赖于NOX 2（NADPH氧化酶2）介导的CaMK II MM 281/2氧化。糖尿病导致更大的Ca 2+渗漏、RyR 2 S2814磷酸化、电生理学重塑和对体内心律失常的易感性增加，需要CaMKII活化，主要通过S280 O-GlcNAc酰化，较少通过MM 281/2氧化。这些影响存在于正常葡萄糖下的肌细胞中，但在体内高循环葡萄糖下加剧。糖尿病患者PLB（受磷蛋白）O-GlcNAc化水平升高，与PLB S16磷酸化水平降低一致。丹曲林可逆转CaMKII依赖性促红细胞释放RyR介导的Ca 2+渗漏，也可预防高血糖诱导的APD延长和延迟后除极。我们发现，CaMKII-S280 O-GlcNAc化是糖尿病高血糖症中心律失常易感性增加所必需的，这可能会因额外的Ang II-NOX 2-CaMKII MM 281/2氧化途径而恶化。CaMKII依赖性RyR 2 S2814磷酸化显著增加促钙渗漏，PLB O-GlcNAc化可能限制肌浆网Ca 2+再摄取，导致糖尿病高血糖症中兴奋-收缩偶联受损和促钙生成。
Supplemental Digital Content is available in the text. Diabetic hyperglycemia is associated with cardiac dysfunction and increased arrhythmia risk, and CaMKII (calcium/calmodulin-dependent protein kinase II) function has been implicated. CaMKII activity is promoted by both oxidation and O-linked β-N-acetylglucosamine (O-GlcNAc) of known CaMKII sites. To investigate which posttranslational modifications occur in human diabetic hearts and how they alter electrophysiological and Ca2+ handling properties in hyperglycemia. We assessed echocardiography, electrophysiology, Ca2+-handling, and protein expression in site-specific CaMKII mutant mice (O-GlcNAc-resistant S280A and oxidation-resistant MM281/2VV knock-ins, and global and cardiac-specific knockouts), in myocytes subjected to acute hyperglycemia and Ang II (angiotensin II) and mice after streptozotocin injections (to induce diabetes). Human patients with diabetes exhibit elevated CaMKII O-GlcNAcylation but not oxidation. In mice, acute hyperglycemia increased spontaneous diastolic Ca2+ sparks and waves and arrhythmogenic action potential changes (prolongation, alternans, and delayed afterdepolarizations), all of which required CaMKII-S280 O-GlcNAcylation. Ang II effects were dependent on NOX2 (NADPH oxidase 2)-mediated CaMKII MM281/2 oxidation. Diabetes led to much greater Ca2+ leak, RyR2 S2814 phosphorylation, electrophysiological remodeling, and increased susceptibility to in vivo arrhythmias, requiring CaMKII activation, predominantly via S280 O-GlcNAcylation and less via MM281/2 oxidation. These effects were present in myocytes at normal glucose but were exacerbated with the in vivo high circulating glucose. PLB (phospholamban) O-GlcNAcylation was increased and coincided with reduced PLB S16 phosphorylation in diabetes. Dantrolene, which reverses CaMKII-dependent proarrhythmic RyR-mediated Ca2+ leak, also prevented hyperglycemia-induced APD prolongation and delayed afterdepolarizations. We found that CaMKII-S280 O-GlcNAcylation is required for increased arrhythmia susceptibility in diabetic hyperglycemia, which can be worsened by an additional Ang II-NOX2-CaMKII MM281/2 oxidation pathway. CaMKII-dependent RyR2 S2814 phosphorylation markedly increases proarrhythmic Ca2+ leak and PLB O-GlcNAcylation may limit sarcoplasmic reticulum Ca2+ reuptake, leading to impaired excitation-contraction coupling and arrhythmogenesis in diabetic hyperglycemia.