Humanized Dsp ACM Mouse Model Displays Stress-Induced Cardiac Electrical and Structural Phenotypes.
Humanized Dsp ACM Mouse Model Displays Stress-Induced Cardiac Electrical and Structural Phenotypes.
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作者：
致心律失常的心肌病(ACM)是一种遗传性疾病，其特征是纤维脂肪浸润，室性心律失常和猝死的倾向增加。桥粒基因的遗传变异与ACM有关。不完全外显是ACM家庭的一个共同特征，使人们对外部应激源如何促进疾病发展的理解复杂化。为了分析遗传学和外部应激源在ACM进展中的双重作用，我们通过将人类R451G变体的小鼠等价物引入内源性桥粒蛋白(DspR451G/+)，建立了首批ACM小鼠模型之一，该模型概括了人类的变体。这种变异的纯合子小鼠表现出胚胎致死性。虽然DspR451G/+小鼠在DSP表达减少的情况下存活，但在基线时没有发现明显的致心律失常或结构性表型。然而，增加后负荷会导致心功能降低，心腔扩张增加，并加速进展为心力衰竭。此外，在儿茶酚胺能激发后，DspR451G/+小鼠表现出频繁和延长的心律失常事件。最后，在基线的DspR451G/+小鼠中注意到连接蛋白-43的异常定位，在压力超负荷的心脏应激后变得更加明显。综上所述，心血管应激是揭示ACM小鼠模型中最早的人源化ACM模型之一的电和结构表型的关键触发因素。
Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder characterized by fibro-fatty infiltration with an increased propensity for ventricular arrhythmias and sudden death. Genetic variants in desmosomal genes are associated with ACM. Incomplete penetrance is a common feature in ACM families, complicating the understanding of how external stressors contribute towards disease development. To analyze the dual role of genetics and external stressors on ACM progression, we developed one of the first mouse models of ACM that recapitulates a human variant by introducing the murine equivalent of the human R451G variant into endogenous desmoplakin (DspR451G/+). Mice homozygous for this variant displayed embryonic lethality. While DspR451G/+ mice were viable with reduced expression of DSP, no presentable arrhythmogenic or structural phenotypes were identified at baseline. However, increased afterload resulted in reduced cardiac performance, increased chamber dilation, and accelerated progression to heart failure. In addition, following catecholaminergic challenge, DspR451G/+ mice displayed frequent and prolonged arrhythmic events. Finally, aberrant localization of connexin-43 was noted in the DspR451G/+ mice at baseline, becoming more apparent following cardiac stress via pressure overload. In summary, cardiovascular stress is a key trigger for unmasking both electrical and structural phenotypes in one of the first humanized ACM mouse models.
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影响因子：
6
作者：
El Refaey M;Coles S;Musa H;Stevens TL;Wallace MJ;Murphy NP;Antwi-Boasiako S;Young LJ;Manring HR;Curran J;Makara MA;Sas K;Han M;Koenig SN;Skaf M;Kline CF;Janssen PML;Accornero F;Borzok MA;Mohler PJ
通讯作者：
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影响因子：
5.2
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通讯作者：
Anker MS
影响因子：
3.5
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Shou, Weinian
河马途径被激活，是心律失常性心肌病中脂肪形成的因果机制。
影响因子：
20.1
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Chen SN;Gurha P;Lombardi R;Ruggiero A;Willerson JT;Marian AJ
通讯作者：
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影响因子：
5.3
作者：
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通讯作者：
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