Myofilament Alterations Associated with Human R14del-Phospholamban Cardiomyopathy.
Myofilament Alterations Associated with Human R14del-Phospholamban Cardiomyopathy.
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DOI：
10.3390/ijms24032675
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发表时间：
2023-01-31
影响因子：
5.6
通讯作者：
Sadayappan, Sakthivel
中科院分区：
文献类型：
--
作者：
Kumar, Mohit;Haghighi, Kobra;Koch, Sheryl;Rubinstein, Jack;Stillitano, Francesca;Hajjar, Roger J.;Kranias, Evangelia G.;Sadayappan, Sakthivel
受磷蛋白（PLN）是心脏收缩力的主要调节因子，该基因的人类突变引起遗传性心肌病。精氨酸14的缺失是最普遍的心肌病相关突变，并且它已与心肌病和早期死亡相关联。对PLN人源化突变小鼠的研究表明，心律失常的倾向增加，但在没有任何明显结构重塑的情况下，与R14 del-PLN心功能障碍相关的潜在细胞机制仍不清楚。本研究阐述了肌丝在R14 del-PLN的设置中的特定作用以及R14 del-PLN在心脏中的长期作用。最大力在左心室和右心室的去皮心肌细胞中被抑制，但这种作用在R14 del-PLN小鼠的右心室中更明显。此外，在突变小鼠的两个心室肌丝的Ca 2+敏感性增加。然而，R14 del-PLN对收缩参数的抑制作用可以用正性肌力药物Omecamtiv Mecarbil（一种肌球蛋白激活剂）逆转。在12月龄时，对应于R14 del-PLN患者的平均症状年龄，右心室R14 del-PLN心肌细胞的收缩参数和Ca 2+瞬变显著降低。超声心动图没有发现任何心脏功能或重塑的改变，尽管组织学和电子显微镜分析表明突变心脏有细微的改变。这些发现表明，无论是异常的心肌细胞钙循环和异常收缩性仍然是特定的右心室在长期。此外，肌丝活性改变是R14 del-PLN突变心脏的早期特征，正性肌力药物Omecamtiv Mecarbil可能有益于治疗R14 del-PLN心肌病。
Phospholamban (PLN) is a major regulator of cardiac contractility, and human mutations in this gene give rise to inherited cardiomyopathies. The deletion of Arginine 14 is the most-prevalent cardiomyopathy-related mutation, and it has been linked to arrhythmogenesis and early death. Studies in PLN-humanized mutant mice indicated an increased propensity to arrhythmias, but the underlying cellular mechanisms associated with R14del-PLN cardiac dysfunction in the absence of any apparent structural remodeling remain unclear. The present study addressed the specific role of myofilaments in the setting of R14del-PLN and the long-term effects of R14del-PLN in the heart. Maximal force was depressed in skinned cardiomyocytes from both left and right ventricles, but this effect was more pronounced in the right ventricle of R14del-PLN mice. In addition, the Ca2+ sensitivity of myofilaments was increased in both ventricles of mutant mice. However, the depressive effects of R14del-PLN on contractile parameters could be reversed with the positive inotropic drug omecamtiv mecarbil, a myosin activator. At 12 months of age, corresponding to the mean symptomatic age of R14del-PLN patients, contractile parameters and Ca2+ transients were significantly depressed in the right ventricular R14del-PLN cardiomyocytes. Echocardiography did not reveal any alterations in cardiac function or remodeling, although histological and electron microscopy analyses indicated subtle alterations in mutant hearts. These findings suggest that both aberrant myocyte calcium cycling and aberrant contractility remain specific to the right ventricle in the long term. In addition, altered myofilament activity is an early characteristic of R14del-PLN mutant hearts and the positive inotropic drug omecamtiv mecarbil may be beneficial in treating R14del-PLN cardiomyopathy.
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影响因子：
--
作者：
Gerull B;Brodehl A
通讯作者：
Brodehl A
影响因子：
5.4
作者：
Hall C;Gehmlich K;Denning C;Pavlovic D
通讯作者：
Pavlovic D
影响因子：
5
作者：
Huke S;Knollmann BC
通讯作者：
Knollmann BC
影响因子：
24
作者：
Felker, G. Michael;Solomon, Scott D.;Teerlink, John R.
通讯作者：
Teerlink, John R.
DOI：
10.1073/pnas.0510519103
发表时间：
2006-01-31
影响因子：
11.1
作者：
Haghighi, K;Kolokathis, F;Kranias, EG
通讯作者：
Kranias, EG