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Genetically induced moderate inhibition of 20S proteasomes in cardiomyocytes facilitates heart failure in mice during systolic overload

机译：遗传诱导的对心肌细胞中20S蛋白酶体的适度抑制促进小鼠心脏收缩过度期间的心力衰竭

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The in vivo function status of the ubiquitin-proteasome system (UPS) in pressure overloaded hearts remains undefined. Cardiotoxicity was observed during proteasome inhibitor chemotherapy, especially in those with preexisting cardiovascular conditions; however, proteasome inhibition (PsmI) was also suggested by some experimental studies as a potential therapeutic strategy to curtail cardiac hypertrophy. Here we used genetic approaches to probe cardiac UPS performance and determine the impact of cardiomyocyte-restricted PsmI (CR-PsmI) on cardiac responses to systolic overload. Transgenic mice expressing an inverse reporter of the UPS (GFPdgn) were subject to transverse aortic constriction (TAC) to probe myocardial UPS performance during systolic overload. Mice with or without moderate CR-PsmI were subject to TAC and temporally characterized for cardiac responses to moderate and severe systolic overload. After moderate TAC (pressure gradient: ~40mmHg), cardiac UPS function was upregulated during the first two weeks but turned to functional insufficiency between 6 and 12 weeks as evidenced by the dynamic changes in GFPdgn protein levels, proteasome peptidase activities, and total ubiquitin conjugates. Severe TAC (pressure gradients >60mmHg) led to UPS functional insufficiency within a week. Moderate TAC elicited comparable hypertrophic responses between mice with and without genetic CR-PsmI but caused cardiac malfunction in CR-PsmI mice significantly earlier than those without CR-PsmI. In mice subject to severe TAC, CR-PsmI inhibited cardiac hypertrophy but led to rapidly progressed heart failure and premature death, associated with a pronounced increase in cardiomyocyte death. It is concluded that cardiac UPS function is dynamically altered, with the initial brief upregulation of proteasome function being adaptive; and CR-PsmI facilitates cardiac malfunction during systolic overload.
机译：压力超负荷心脏中泛素-蛋白酶体系统（UPS）的体内功能状态仍然不确定。在蛋白酶体抑制剂化疗期间观察到了心脏毒性，尤其是在那些已经患有心血管疾病的患者中；然而，一些实验研究也提出了蛋白酶体抑制（PsmI）作为减少心脏肥大的潜在治疗策略。在这里，我们使用遗传方法来探查心脏UPS的性能，并确定心肌细胞限制性PsmI（CR-PsmI）对心脏对收缩期超负荷反应的影响。表达UPS反向报告基因（GFPdgn）的转基因小鼠接受主动脉横向收缩（TAC），以探查收缩期超负荷期间的心肌UPS性能。患有或不患有中度CR-PsmI的小鼠均接受TAC治疗，并在时间上表征对中度和重度收缩期超负荷的心脏反应。中度TAC（压力梯度：〜40mmHg）后，心脏UPS功能在前两周上调，但在GFPdgn蛋白水平，蛋白酶体肽酶活性和总遍在蛋白缀合物的动态变化中证明，在6至12周之间转为功能不全。 。严重的TAC（压力梯度> 60mmHg）导致UPS在一周内功能不足。中度TAC在有和没有遗传CR-PsmI的小鼠之间引起可比的肥大反应，但在CR-PsmI小鼠中引起心脏功能障碍的时间明显早于没有CR-PsmI的小鼠。在患有严重TAC的小鼠中，CR-PsmI抑制心脏肥大，但导致快速发展的心力衰竭和过早死亡，并伴有心肌细胞死亡的明显增加。结论是，心脏UPS功能是动态变化的，蛋白酶体功能最初的短暂上调是适应性的； CR-PsmI可促进心脏收缩过度期间的心脏功能障碍。

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