DWORF Extends Life Span in a PLN-R14del Cardiomyopathy Mouse Model by Reducing Abnormal Sarcoplasmic Reticulum Clusters.
DWORF Extends Life Span in a PLN-R14del Cardiomyopathy Mouse Model by Reducing Abnormal Sarcoplasmic Reticulum Clusters.
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DOI：
10.1161/circresaha.123.323304
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发表时间：
2023-12-08
影响因子：
20.1
通讯作者：
Sillje, Herman H. W.
中科院分区：
文献类型：
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作者：
Stege, Nienke M.;Eijgenraam, Tim R.;Oliveira Nunes Teixeira, Vivian;Feringa, Anna M.;Schouten, Elisabeth M.;Kuster, Diederik W. D.;van der Velden, Jolanda;Wolters, Anouk H. G.;Giepmans, Ben N. G.;Makarewich, Catherine A.;Bassel-Duby, Rhonda;Olson, Eric N.;de Boer, Rudolf A.;Sillje, Herman H. W.
PLN（磷蛋白）基因的p.a g14del变异引起心肌病，导致严重的心力衰竭。钙处理缺陷和核周PLN聚集都被认为是这种疾病的病理驱动因素。侏儒开放阅读框（DWORF）已被证明可以抵消PLN在sarco/内质网（S/ER）中的钙处理调节功能。在这里，我们研究了DWORF在这种心肌病中的潜在疾病调节作用及其对钙处理和PLN聚集的影响。我们研究了PLN-R14del小鼠模型，该模型发生与人类患者相似的心肌病，并探索心脏DWORF过表达是否可以延缓心脏恶化。为此，使用携带DWORF转基因的R14Δ/Δ（纯合子PLN-R14del）小鼠（R14Δ/ΔDWORFTg [R14Δ/Δ携带DWORF转基因的小鼠]）。严重心力衰竭的R14Δ/Δ小鼠心脏中DWORF表达受到抑制。恢复R14Δ/Δ小鼠DWORF表达可延缓心脏纤维化和心力衰竭，延长寿命2倍（从8周到18周）。DWORF在野生型PLN分离心肌细胞中加速肌浆网钙的再摄取和舒张，但在R14Δ/Δ心肌细胞中，肌浆网钙的再摄取和舒张已经增强，R14Δ/Δ和R14Δ/ΔDWORFTg之间没有差异。相反，DWORF过表达延缓了核周大致病性PLN簇的出现和形成。仔细检查发现，在R14Δ/Δ小鼠和人类p.a g14del PLN心脏组织中，肌浆网标记物与这些PLN聚集物共定位，因此这些先前称为聚集物由异常组织的S/ER组成。在PLN-R14del心肌病中，这种异常的S/ER组织导致心肌细胞损失和替代纤维化，从而导致心功能障碍。紊乱的S/ER是人类和小鼠PLN-R14del心肌病的主要特征，并导致心肌细胞死亡。DWORF过表达通过减少异常S/ER簇，延缓R14Δ/Δ小鼠PLN-R14del心肌病进展并延长寿命。
The p.Arg14del variant of the PLN (phospholamban) gene causes cardiomyopathy, leading to severe heart failure. Calcium handling defects and perinuclear PLN aggregation have both been suggested as pathological drivers of this disease. Dwarf open reading frame (DWORF) has been shown to counteract PLN regulatory calcium handling function in the sarco/endoplasmic reticulum (S/ER). Here, we investigated the potential disease-modulating action of DWORF in this cardiomyopathy and its effects on calcium handling and PLN aggregation. We studied a PLN-R14del mouse model, which develops cardiomyopathy with similar characteristics as human patients, and explored whether cardiac DWORF overexpression could delay cardiac deterioration. To this end, R14Δ/Δ (homozygous PLN-R14del) mice carrying the DWORF transgene (R14Δ/ΔDWORFTg [R14Δ/Δ mice carrying the DWORF transgene]) were used. DWORF expression was suppressed in hearts of R14Δ/Δ mice with severe heart failure. Restoration of DWORF expression in R14Δ/Δ mice delayed cardiac fibrosis and heart failure and increased life span >2-fold (from 8 to 18 weeks). DWORF accelerated sarcoplasmic reticulum calcium reuptake and relaxation in isolated cardiomyocytes with wild-type PLN, but in R14Δ/Δ cardiomyocytes, sarcoplasmic reticulum calcium reuptake and relaxation were already enhanced, and no differences were detected between R14Δ/Δ and R14Δ/ΔDWORFTg. Rather, DWORF overexpression delayed the appearance and formation of large pathogenic perinuclear PLN clusters. Careful examination revealed colocalization of sarcoplasmic reticulum markers with these PLN clusters in both R14Δ/Δ mice and human p.Arg14del PLN heart tissue, and hence these previously termed aggregates are comprised of abnormal organized S/ER. This abnormal S/ER organization in PLN-R14del cardiomyopathy contributes to cardiomyocyte cell loss and replacement fibrosis, consequently resulting in cardiac dysfunction. Disorganized S/ER is a major characteristic of PLN-R14del cardiomyopathy in humans and mice and results in cardiomyocyte death. DWORF overexpression delayed PLN-R14del cardiomyopathy progression and extended life span in R14Δ/Δ mice, by reducing abnormal S/ER clusters.
影响因子：
16.6
作者：
通讯作者：
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