Genetic Inhibition of Mitochondrial Permeability Transition Pore Exacerbates Ryanodine Receptor 2 Dysfunction in Arrhythmic Disease.
Genetic Inhibition of Mitochondrial Permeability Transition Pore Exacerbates Ryanodine Receptor 2 Dysfunction in Arrhythmic Disease.
复制标题
线粒体通透性过渡孔的遗传抑制加剧了心律失常疾病中ryanodine受体2功能障碍。
作者：
线粒体通透性转换孔（mPTP）的短暂开放模式充当钙（Ca2+）释放阀，以防止线粒体Ca2+（mCa2+）过载。儿茶酚胺能多形性室性心动过速 (CPVT) 是一种由兰尼碱受体 2 (RyR2) 的 Ca2+ 释放通道复合体突变引起的应激性心律失常综合征。我们假设抑制 CPVT 中 mPTP 的开放会加剧疾病表型。通过将 CASQ2 敲除 (KO) 的 CPVT 模型与缺失 CypD（mPTP 激活剂）的小鼠杂交，生成双 KO 模型 (DKO)。采用超声心动图、心脏组织学和活细胞成像来评估心脏病理学的严重程度。进行蛋白质印迹和 RNAseq 来评估各种信号通路的贡献。尽管有报道称心律失常加剧，但 DKO 模型并未表现出病理性重塑。低起搏频率下，肌细胞 Ca2+ 处理与 CASQ2 KO 小鼠相似。然而，在 DKO 中检测到 ROS 产生增加、CaMKII 通路激活和 RyR2 过度磷酸化。转录组分析确定了与 DKO 中电不稳定性相关的基因表达谱的改变。我们的研究提供了证据，表明 mPTP 的基因抑制通过增加 CaMKII 通路的激活和随后的 RyR2 过度磷酸化而加剧 CPVT 中的 RyR2 功能障碍。
The brief opening mode of the mitochondrial permeability transition pore (mPTP) serves as a calcium (Ca2+) release valve to prevent mitochondrial Ca2+ (mCa2+) overload. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced arrhythmic syndrome due to mutations in the Ca2+ release channel complex of ryanodine receptor 2 (RyR2). We hypothesize that inhibiting the mPTP opening in CPVT exacerbates the disease phenotype. By crossbreeding a CPVT model of CASQ2 knockout (KO) with a mouse missing CypD, an activator of mPTP, a double KO model (DKO) was generated. Echocardiography, cardiac histology, and live-cell imaging were employed to assess the severity of cardiac pathology. Western blot and RNAseq were performed to evaluate the contribution of various signaling pathways. Although exacerbated arrhythmias were reported, the DKO model did not exhibit pathological remodeling. Myocyte Ca2+ handling was similar to that of the CASQ2 KO mouse at a low pacing frequency. However, increased ROS production, activation of the CaMKII pathway, and hyperphosphorylation of RyR2 were detected in DKO. Transcriptome analysis identified altered gene expression profiles associated with electrical instability in DKO. Our study provides evidence that genetic inhibition of mPTP exacerbates RyR2 dysfunction in CPVT by increasing activation of the CaMKII pathway and subsequent hyperphosphorylation of RyR2.
登录
查看更多内容
影响因子：
8.8
作者：
Kwong JQ;Lu X;Correll RN;Schwanekamp JA;Vagnozzi RJ;Sargent MA;York AJ;Zhang J;Bers DM;Molkentin JD
通讯作者：
Molkentin JD
影响因子：
37.8
作者：
Bezzerides, Vassilios J.;Caballero, Ana;Pu, William T.
通讯作者：
Pu, William T.
影响因子：
4
作者：
Gordan, Richard;Fefelova, Nadezhda;Xie, Lai-Hua
通讯作者：
Xie, Lai-Hua
影响因子：
4.6
作者：
Bonilla, Ingrid M.;Belevych, Andriy E.;Gyorke, Sandor
通讯作者：
Gyorke, Sandor
影响因子：
64.8
作者：
Baines, CP;Kaiser, RA;Molkentin, JD
通讯作者：
Molkentin, JD