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心肌病中肌浆素表达的激活及钙循环的改变

Activation of sarcolipin expression and altered calcium cycling in cardiomyopathy.

作者信息

Morales Rodriguez Blanca, Domínguez-Rodríguez Alejandro, Benitah Jean-Pierre, Lefebvre Florence, Marais Thibaut, Mougenot Nathalie, Beauverger Philippe, Bonne Gisèle, Briand Véronique, Gómez Ana-María, Muchir Antoine

机构信息

Sorbonne Université, INSERM UMRS974, Paris, France.

Sanofi R&D, Chilly-Mazarin, France.

出版信息

Biochem Biophys Rep. 2020 May 18;22:100767. doi: 10.1016/j.bbrep.2020.100767. eCollection 2020 Jul.

DOI:10.1016/j.bbrep.2020.100767
PMID:32490213
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7261707/
Abstract

Cardiomyopathy caused by A-type lamins gene () mutations ( cardiomyopathy) is associated with dysfunction of the heart, often leading to heart failure. cardiomyopathy is highly penetrant with bad prognosis with no specific therapy available. Searching for alternative ways to halt the progression of cardiomyopathy, we studied the role of calcium homeostasis in the evolution of this disease. We showed that sarcolipin, an inhibitor of the sarco/endoplasmic reticulum (SR) Ca ATPase (SERCA) was abnormally elevated in the ventricular cardiomyocytes of mutated mice compared with wild type mice, leading to an alteration of calcium handling. This occurs early in the progression of the disease, when the left ventricular function was not altered. We further demonstrated that down regulation of sarcolipin using adeno-associated virus (AAV) 9-mediated RNA interference delays cardiac dysfunction in mouse model of cardiomyopathy. These results showed a novel role for sarcolipin on calcium homeostasis in heart and open perspectives for future therapeutic interventions to cardiomyopathy.

摘要

由A型核纤层蛋白基因（）突变引起的心肌病（心肌病）与心脏功能障碍有关，常导致心力衰竭。心肌病具有高度的外显率，预后不良，且没有可用的特异性治疗方法。为了寻找阻止心肌病进展的替代方法，我们研究了钙稳态在这种疾病发展过程中的作用。我们发现，与野生型小鼠相比，突变小鼠心室心肌细胞中肌浆网/内质网（SR）Ca ATP酶（SERCA）的抑制剂肌浆蛋白异常升高，导致钙处理改变。这种情况在疾病进展早期就会出现，此时左心室功能尚未改变。我们进一步证明，使用腺相关病毒（AAV）9介导的RNA干扰下调肌浆蛋白可延缓心肌病小鼠模型的心脏功能障碍。这些结果显示了肌浆蛋白在心脏钙稳态中的新作用，并为未来治疗心肌病的干预措施开辟了前景。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/237d/7261707/c7fee705d433/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/237d/7261707/f10f7937fbb8/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/237d/7261707/7e92355eb184/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/237d/7261707/480ce0cb05f5/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/237d/7261707/6250fa96e936/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/237d/7261707/416b1b416d9d/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/237d/7261707/60fb0301c70e/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/237d/7261707/c7fee705d433/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/237d/7261707/f10f7937fbb8/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/237d/7261707/7e92355eb184/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/237d/7261707/480ce0cb05f5/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/237d/7261707/6250fa96e936/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/237d/7261707/416b1b416d9d/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/237d/7261707/60fb0301c70e/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/237d/7261707/c7fee705d433/gr7.jpg

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2
Truncated dystrophin ameliorates the dystrophic phenotype of mdx mice by reducing sarcolipin-mediated SERCA inhibition.截断型肌营养不良蛋白通过减少肌浆网钙 ATP 酶抑制因子介导的肌浆网钙 ATP 酶抑制作用，改善 mdx 小鼠的肌营养不良表型。
Biochem Biophys Res Commun. 2018 Oct 20;505(1):51-59. doi: 10.1016/j.bbrc.2018.09.039. Epub 2018 Sep 17.
3
Sarcolipin deletion in mdx mice impairs calcineurin signalling and worsens dystrophic pathology.
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Eur Heart J. 2024 Sep 14;45(35):3296. doi: 10.1093/eurheartj/ehae485.
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