Primary proteasome inhibition results in cardiac dysfunction
Primary proteasome inhibition results in cardiac dysfunction
复制标题
DOI：
10.1093/eurjhf/hft034
复制
发表时间：
2013-06-01
影响因子：
18.2
通讯作者：
Lerman, Amir
中科院分区：
文献类型：
--
作者：
Herrmann, Joerg;Wohlert, Christine;Lerman, Amir
蛋白酶体阻止细胞内蛋白质的积累，其损伤可导致结构和功能的改变，如先前的一项研究中所指出的冠状血管。利用相同的模型，本研究旨在验证慢性蛋白酶体抑制（PSI）也导致心脏结构和功能改变的假设。将雌性家猪随机分为两组，分别饲喂不添加(N)的正常饲粮和每周2次皮下注射蛋白酶体抑制剂MLN-273 （0.08 mg/kg, N PSI，每组N 5）。11周后通过电子束计算机断层扫描获得心脏结构和功能以及心肌灌注和微血管通透性对腺苷和多巴酚丁胺的反应。随后的离体心肌分析包括免疫印迹、免疫染色、TUNEL（末端脱氧核苷酸转移酶dUTP缺口末端标记）、马松三色和刚果红染色。与N组相比，N组左室质量增加（106.5 16.4 g比183.1 24.2 g, P < 0.05）。N PSI组比N PSI组舒张早晚期充盈率升高（3.5 0.6比1.8 0.1,P 0.05）。心力衰竭倾向于较低（分别为46 12和53 9），心输出量显著低于N组（2.9 1.1比4.7 1.1 L/min, P < 0.05）。组织分析显示，PSI组存在蛋白酶体底物、细胞凋亡和纤维化的积累。与N组相比，N组心肌灌注反应降低，微血管通透性增加。目前的研究表明，慢性蛋白酶体抑制影响心血管系统，导致心脏的功能和结构改变，与肥厚限制性心肌病表型一致。
The proteasome prevents the intracellular accumulation of proteins and its impairment can lead to structural and functional alterations, as noted for the coronary vasculature in a previous study. Utilizing the same model, this study was designed to test the hypothesis that chronic proteasome inhibition (PSI) also leads to structural and functional changes of the heart.Female domestic pigs were randomized to a normal diet without (N) or with twice-weekly subcutaneous injections of the proteasome inhibitor MLN-273 (0.08 mg/kg, N PSI, n 5 each group). In vivo data on cardiac structure and function as well as myocardial perfusion and microvascular permeability response to adenosine and dobutamine were obtained by electron beam computed tomography after 11 weeks. Subsequent ex vivo myocardial analyses included immunoblotting, immunostaining, TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labelling), Masson trichrome, and Congo red staining. Compared with N, an increase in LV mass was observed in N PSI (106.5 16.4 g vs. 183.1 24.2 g, P 0.05). The early to late diastolic filling ratio was increased in N PSI vs. N (3.5 0.6 vs. 1.8 0.1, P 0.05). The EF tended to be lower (46 12 and 53 9, respectively) and cardiac output was significantly lower in N PSI than in N (2.9 1.1 vs. 4.7 1.1 L/min, P 0.05). Tissue analyses demonstrated an accumulation of proteasome substrates, apoptosis, and fibrosis in the PSI group. Compared with N, the myocardial perfusion response was reduced and microvascular permeability was increased in N PSI.The current study demonstrates that chronic proeasome inhibition affects the cardiovascular system, leading to functional and structural alteration of the heart consistent with a hypertrophicrestrictive cardiomyopathy phenotype.