Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart.
Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart.
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DOI：
10.7554/elife.84088
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发表时间：
2023-05-19
期刊：
影响因子：
7.7
通讯作者：
Koren G
中科院分区：
文献类型：
--
作者：
Baggett BC;Murphy KR;Sengun E;Mi E;Cao Y;Turan NN;Lu Y;Schofield L;Kim TY;Kabakov AY;Bronk P;Qu Z;Camelliti P;Dubielecka P;Terentyev D;Del Monte F;Choi BR;Sedivy J;Koren G
心肌梗死（MI）后进行性组织重构促进心律失常。这一过程在年轻动物中得到了很好的研究，但对老年动物的促排卵变化知之甚少。衰老细胞随着年龄的增长而积累，并加速与年龄相关的疾病。随着年龄的增长，衰老细胞干扰心脏功能和MI后的结果，但尚未在较大的动物中进行研究，其机制尚不清楚。具体而言，衰老时程的年龄相关变化以及炎症和纤维化的相关变化尚未得到很好的理解。此外，衰老的细胞和全身作用及其炎症环境在影响随着年龄的增长而发生的血管生成中的作用尚不清楚，特别是在心脏电生理学与人类比以前研究的动物模型更相似的大型动物模型中。在这里，我们研究了衰老在调节炎症，纤维化和血管生成中的作用，在年轻和老年梗死兔。与年轻兔相比，老年兔的围手术期死亡率和梗死边缘区（IBZ）的致炎性电生理重塑增加。对老年梗死区的研究显示，在12周的时间过程中，肌成纤维细胞持续衰老，炎症信号增加。老年兔衰老的IBZ肌成纤维细胞似乎与心肌细胞偶联，我们的计算模型显示，衰老的肌成纤维细胞-心肌细胞偶联延长动作电位时程（APD），并促进传导阻滞，从而允许心律失常。老年梗塞的人心室显示出与老年兔一致的衰老水平，并且衰老的肌成纤维细胞也与IBZ肌细胞偶联。我们的研究结果表明，针对衰老细胞的治疗干预可能会减轻心肌梗死后心律失常与年龄。
Progressive tissue remodeling after myocardial infarction (MI) promotes cardiac arrhythmias. This process is well studied in young animals, but little is known about pro-arrhythmic changes in aged animals. Senescent cells accumulate with age and accelerate age-associated diseases. Senescent cells interfere with cardiac function and outcome post-MI with age, but studies have not been performed in larger animals, and the mechanisms are unknown. Specifically, age-associated changes in timecourse of senescence and related changes in inflammation and fibrosis are not well understood. Additionally, the cellular and systemic role of senescence and its inflammatory milieu in influencing arrhythmogenesis with age is not clear, particularly in large animal models with cardiac electrophysiology more similar to humans than previously studied animal models. Here, we investigated the role of senescence in regulating inflammation, fibrosis, and arrhythmogenesis in young and aged infarcted rabbits. Aged rabbits exhibited increased peri-procedural mortality and arrhythmogenic electrophysiological remodeling at the infarct border zone (IBZ) compared to young rabbits. Studies of the aged infarct zone revealed persistent myofibroblast senescence and increased inflammatory signaling over a 12-week timecourse. Senescent IBZ myofibroblasts in aged rabbits appear to be coupled to myocytes, and our computational modeling showed that senescent myofibroblast-cardiomyocyte coupling prolongs action potential duration (APD) and facilitates conduction block permissive of arrhythmias. Aged infarcted human ventricles show levels of senescence consistent with aged rabbits, and senescent myofibroblasts also couple to IBZ myocytes. Our findings suggest that therapeutic interventions targeting senescent cells may mitigate arrhythmias post-MI with age.
影响因子：
4
作者：
Kabakov AY;Sengun E;Lu Y;Roder K;Bronk P;Baggett B;Turan NN;Moshal KS;Koren G
通讯作者：
Koren G
影响因子：
2.9
作者：
Dai W;Jiang Y;Chen K;Qiu J;Sun J;Zhang W;Zhou X;Huang N;Li Y;Li W
通讯作者：
Li W