Oxidized CaMKII causes cardiac sinus node dysfunction in mice
Oxidized CaMKII causes cardiac sinus node dysfunction in mice
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DOI：
10.1172/jci57833
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发表时间：
2011-08-01
影响因子：
15.9
通讯作者：
Anderson, Mark E.
中科院分区：
文献类型：
--
作者：
Swaminathan, Paari Dominic;Purohit, Anil;Anderson, Mark E.
窦房结功能障碍(SND)是一种与心源性猝死相关的主要公共卫生问题，需要外科植入人工起搏器。然而，人们对SND的分子和细胞机制知之甚少。大多数SND发生在心力衰竭和高血压的背景下，这些情况以循环血管紧张素II(Ang II)升高和氧化应激增加为标志。在这里，我们表明氧化钙调蛋白激酶II(OX-CaMKII)是患者和狗的SND的生物标志物，也是小鼠的疾病决定因素。在野生型小鼠中，Ang II通过激活NADPH氧化酶引起窦房结(SAN)细胞氧化，导致OX-CaMKII、SAN细胞凋亡和SND增加。缺乏功能性NADPH氧化酶的p47(--)小鼠和心肌或SAN靶向CaMKII抑制的小鼠对SAN凋亡和SND具有高度的抵抗力，提示OX-CaMKII触发的SAN细胞死亡参与了SND的发生。我们开发了一个窦房结的计算模型，该模型表明，低于临界阈值的窦房结细胞的丢失通过阻止正常脉冲的形成和传播而导致SND。这些数据为理解SND提供了新的分子和机制信息，并提示靶向抑制CaMKII可能有助于预防高危患者的SND。
Sinus node dysfunction (SND) is a major public health problem that is associated with sudden cardiac death and requires surgical implantation of artificial pacemakers. However, little is known about the molecular and cellular mechanisms that cause SND. Most SND occurs in the setting of heart failure and hypertension, conditions that are marked by elevated circulating angiotensin II (Ang II) and increased oxidant stress. Here, we show that oxidized calmodulin kinase II (ox-CaMKII) is a biomarker for SND in patients and dogs and a disease determinant in mice. In wild-type mice, Ang II infusion caused sinoatrial nodal (SAN) cell oxidation by activating NADPH oxidase, leading to increased ox-CaMKII, SAN cell apoptosis, and SND. p47(- -) mice lacking functional NADPH oxidase and mice with myocardial or SAN-targeted CaMKII inhibition were highly resistant to SAN apoptosis and SND, suggesting that ox-CaMKII-triggered SAN cell death contributed to SND. We developed a computational model of the sinoatrial node that showed that a loss of SAN cells below a critical threshold caused SND by preventing normal impulse formation and propagation. These data provide novel molecular and mechanistic information to understand SND and suggest that targeted CaMKII inhibition may be useful for preventing SND in high-risk patients.