Doxycycline attenuates protein aggregation in cardiomyocytes and improves survival of a mouse model of cardiac proteinopathy.
Doxycycline attenuates protein aggregation in cardiomyocytes and improves survival of a mouse model of cardiac proteinopathy.
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DOI：
10.1016/j.jacc.2010.01.075
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发表时间：
2010-10-19
影响因子：
24
通讯作者：
Wang, Xuejun
中科院分区：
文献类型：
--
作者：
Zheng, Hanqiao;Tang, Mingxin;Zheng, Qingwen;Kumarapeli, Asangi R. K.;Horak, Kathleen M.;Tian, Zongwen;Wang, Xuejun
本临床前研究的目的是评估多西环素（Doxy）对结蛋白相关性心肌病（DRC）的治疗效果，并阐明相关的潜在机制。DRC是心脏蛋白质病的一个例证，其特征在于肌浆内蛋白质聚集和心功能不全。目前尚无有效治疗DRC的方法。Doxy显示出减弱非心脏细胞和其他蛋白质病动物模型中错误折叠蛋白质的异常核内聚集和毒性。采用转基因表达人DRC连锁错义突变体α B-晶体蛋白（CryABR 120 G）的小鼠和培养的新生大鼠心肌细胞检测Doxy的作用。在8或16周龄时开始通过饮用水（6 mg/ml）给予Doxy。在16周龄时开始的Doxy治疗显著延迟了CryABR 120 G TG小鼠的过早死亡，中位寿命为30.4周（安慰剂组25周，p<0.01）。在另一组CryABR 120 G TG小鼠中，8周龄时开始的Doxy治疗在一个月内显着减轻了心脏肥大。进一步的研究表明，Doxy显著降低了CryABR 120 G TG心脏中CryAB阳性微观聚集体、耐洗涤剂CryAB寡聚体和总泛素化蛋白的丰度。在细胞培养中，Doxy处理剂量依赖性地抑制了微观蛋白聚集体和耐洗涤剂的可溶性CryABR 120 G寡聚体的形成，并逆转了腺病毒介导的CryABR 120 G表达诱导的p62蛋白的上调。Doxy抑制CryABR 120 G诱导的心肌细胞中的异常蛋白质聚集和基于CryABR 120 G的DRC小鼠存活。
The goal of this preclinical study was to assess the therapeutic efficacy of doxycycline (Doxy) for desmin-related cardiomyopathy (DRC) and to elucidate the potential mechanisms involved. DRC, exemplifying cardiac proteinopathy, is characterized by intrasarcoplasmic protein aggregation and cardiac insufficiency. No effective treatment for DRC is presently available. Doxy was shown to attenuate aberrant intranuclear aggregation and toxicity of misfolded proteins in non-cardiac cells and animal models of other proteinopathies. Mice and cultured neonatal rat cardiomyocytes with transgenic (TG) expression of a human DRC-linked missense mutant αB-crystallin (CryABR120G) were used for testing the effect of Doxy. Doxy was administered via drinking water (6 mg/ml) initiated at 8 or 16 weeks of age. Doxy treatment initiated at 16 weeks of age significantly delayed the premature death of CryABR120G TG mice, with a median lifespan of 30.4 weeks (placebo group 25 weeks, p<0.01). In another cohort of CryABR120G TG mice, Doxy treatment initiated at 8 weeks of age significantly attenuated cardiac hypertrophy in one month. Further investigation revealed that Doxy significantly reduced the abundance of CryAB-positive microscopic aggregates, detergent-resistant CryAB oligomers, and total ubiquitinated proteins in CryABR120G TG hearts. In cell culture, Doxy treatment dose-dependently suppressed the formation of both microscopic protein aggregates and detergent-resistant soluble CryABR120G oligomers, and reversed the upregulation of p62 protein induced by adenovirus-mediated CryABR120G expression. Doxy suppresses CryABR120G induced aberrant protein aggregation in cardiomyocytes and prolongs CryABR120G based DRC mouse survival.
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影响因子：
37.8
作者：
Cheung, PY;Sawicki, G;Schulz, R
通讯作者：
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DOI：
10.1124/jpet.107.133975
发表时间：
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影响因子：
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作者：
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作者：
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通讯作者：
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影响因子：
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作者：
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