胆红素调控心肌肥大发生发展的作用及机制

Cardiovascular diseases are one of the most common human diseases with high morbidity and mortality. Myocardial hypertrophy (MH) is a common response of the heart to a variety of cardiovascular stimuli. Pathological MH eventually leads to heart failure, and there is no effective measure for the prevention and treatment of MH. Bilirubin is the final product of heme degradation and its cardioprotective effects have also been suggested by some previous studies. Even though a few reports show that bilirubin exhibits suppressive effect on cardiomyocyte hypertrophy, associated with the reduction of ROS production, the effect of bilirubin on MH and especially the underlying mechanisms remain to be defined. Our earlier studies have found that proteasome inhibitors can inhibit MH. Compared with 20S proteasomes, proteasomal deubiquitinase (DUB) is more selective and specific in regulating the degradation of native cellular proteins. In our previous study, we found that bilirubin potentially inhibits the ubiquitin-proteasome system by targeting 19S proteasome-associated DUBs (UCHL5 and USP14). Therefore, we propose that bilirubin has great potential to inhibit MH by suppressing proteasomal DUBs. In this proposed study, the effect of bilirubin on MH and the important role of bilirubin as an endogenous DUB inhibitor in MH will be investigated. This represents the first time to investigate the relationship between DUB inhibition and MH; if succeeded, this will provide a novel strategy for the development of new drugs to prevent and/or better treat MH.

心血管疾病因其高发病率和高死亡率成为威胁人类健康的严重疾病之一。心肌肥大是许多心血管疾病终末期共同的病理生理改变，心肌过度肥大可导致心力衰竭或心源性猝死，但目前未有针对心肌肥大特异的有效的防治措施。胆红素是体内血红素代谢的终产物，许多研究表明高胆红素血症可以抑制多种心血管疾病的发生发展，也有少量研究发现胆红素可能通过其抗氧化特性阻止心肌肥大的进展，但胆红素与心肌肥大发生发展的关系及其机制还未完全清楚。我们前期研究发现胆红素是一个特异性抑制19S蛋白酶体UCHL5和USP14的去泛素化酶（DUB）抑制剂，结合之前研究发现蛋白酶体抑制剂可以有效抑制心肌肥大，提示胆红素很有可能通过抑制DUB从而发挥对心肌肥大的调控。本项目将全面探讨胆红素对心肌肥大的作用及其DUB抑制效应是否为其调控心肌肥大的关键机制。这是国内外首次对DUB与心肌肥大发生发展的关系进行研究，将为心肌肥大的防治提供新的药物途径。

血红素加氧酶1（HO-1）途径在心肌肥厚中的作用已引起广泛关注，但细胞内机制尚不完全清楚。细胞内胆红素是HO-1催化血红素代谢的终末产物。前期研究发现，胆红素通过作用于泛素-蛋白酶体系统抑制细胞内蛋白降解，本项目利用特异性敲除心脏HO-1的转基因小鼠研究发现，HO-1表达降低后心肌胆红素水平显著降低并伴有心肌肥大；由此，本项目以胸主动脉缩窄建立的心肌肥厚小鼠和Ang II诱导的心肌细胞肥大模型为研究对象，以转基因动物、分子生物学干预为主要技术手段，以心脏功能变化、心肌肥大为主要观察指标发现：（1）HO-1能诱导心肌细胞内胆红素水平增高；（2）利用心肌特异性敲除的转基因动物和氯化血红素等特异性酶诱导剂、抑制剂干预胆红素代谢关键酶HO-1表达，明确细胞内胆红素对肥大心肌细胞的直接保护作用；（3）明确细胞内胆红素能调控心脏MAPK蛋白激酶活性，抑制MAPK家族ERK1/2信号通路活化，抑制心肌肥厚，改善心脏功能的具体分子机制。本研究为明确细胞内胆红素的生理作用、揭示其心肌保护机制提供新线索，为寻找逆转心肌肥厚内源性物质提供新的分子靶标，为筛选新型治疗药物提供实验依据。