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丙磺舒治疗改善了一种新的围产期心肌病小鼠模型的预后。

Probenecid treatment improves outcomes in a novel mouse model of peripartum cardiomyopathy.

机构信息

Division of Cardiovascular Health & Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.

Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.

出版信息

PLoS One. 2020 Mar 27;15(3):e0230386. doi: 10.1371/journal.pone.0230386. eCollection 2020.

DOI:10.1371/journal.pone.0230386
PMID:32218573
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7100971/
Abstract

Probenecid has been used for decades in the treatment of gout but recently has also been found to improve outcomes in patients with heart failure via stimulation of the transient receptor potential vanilloid 2 (TRPV2) channel in cardiomyocytes. This study tested the use of probenecid on a novel mouse model of peripartum cardiomyopathy (PPCM) as a potential treatment option. A human mutation of the human heat shock protein 20 (Hsp20-S10F) in mice has been recently shown to result in cardiomyopathy, when exposed to pregnancies. Treatment with either probenecid or control sucrose water was initiated after the first pregnancy in both wild type and Hsp20-S10F mice. Serial echocardiography was performed during subsequent pregnancies and hearts were collected after the third pregnancies for staining and molecular analysis. Hsp20-S10F mice treated with probenecid had decreased mortality, hypertrophy, TRPV2 expression and molecular parameters of heart failure. Probenecid treatment also decreased apoptosis as evidenced by an increase in the level of Bcl-2/Bax. Probenecid improved survival in a novel mouse model of PPCM and may be an appropriate therapy for humans with PPCM as it has a proven safety and tolerability in patients with heart failure.

摘要

丙磺舒已在痛风治疗中使用了数十年，但最近还被发现通过刺激心肌细胞中的瞬时受体电位香草酸 2 (TRPV2) 通道，改善心力衰竭患者的预后。本研究在围产期心肌病 (PPCM) 的新型小鼠模型中测试了丙磺舒的用途，作为一种潜在的治疗选择。最近的研究表明，当暴露于妊娠时，小鼠中的人类热休克蛋白 20 (Hsp20-S10F) 的人类突变会导致心肌病。在野生型和 Hsp20-S10F 小鼠的第一次妊娠后，开始用丙磺舒或对照蔗糖水进行治疗。在随后的妊娠期间进行了连续的超声心动图检查，并在第三次妊娠后收集心脏进行染色和分子分析。用丙磺舒治疗的 Hsp20-S10F 小鼠死亡率降低、肥大、TRPV2 表达和心力衰竭的分子参数降低。丙磺舒治疗还通过增加 Bcl-2/Bax 的水平减少了细胞凋亡。丙磺舒改善了 PPCM 的新型小鼠模型的存活率，并且可能是 PPCM 患者的合适治疗方法，因为它在心力衰竭患者中具有已证实的安全性和耐受性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/465a/7100971/257b5a07e557/pone.0230386.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/465a/7100971/19df1918104a/pone.0230386.g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/465a/7100971/07b534382b0b/pone.0230386.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/465a/7100971/990de3d567a6/pone.0230386.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/465a/7100971/be17f535c71b/pone.0230386.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/465a/7100971/257b5a07e557/pone.0230386.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/465a/7100971/19df1918104a/pone.0230386.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/465a/7100971/bf5dcf4b47ca/pone.0230386.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/465a/7100971/07b534382b0b/pone.0230386.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/465a/7100971/990de3d567a6/pone.0230386.g004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/465a/7100971/257b5a07e557/pone.0230386.g006.jpg

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本文引用的文献

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Peripartum Cardiomyopathy: JACC State-of-the-Art Review.围生期心肌病：美国心脏病学会临床心脏病学实践中的现状综述。
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TRP Channels Expression Profile in Human End-Stage Heart Failure.TRP 通道在人类终末期心力衰竭中的表达谱。
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丙磺舒对TRPV2调节作用的结构见解。
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