Proteasome inhibition promotes regression of left ventricular hypertrophy
Proteasome inhibition promotes regression of left ventricular hypertrophy
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DOI：
10.1152/ajpheart.00196.2007
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发表时间：
2008-02-01
影响因子：
4.8
通讯作者：
Selzman, Craig H.
中科院分区：
文献类型：
--
作者：
Stansfield, William E.;Tang, Ru-Hang;Selzman, Craig H.
目前对左心室肥厚（LVH）的研究主要集中在其进展和预防或减缓其发展的治疗机制。很少有研究集中在现有LVH的消退或治疗上。核因子-κ B（NF-κ B）是一种炎症转录因子，已被证明参与LVH的发展。我们假设蛋白酶体介导的NF-κ B抑制可以阻止LVH的发展并促进其消退。通过皮下给予异丙肾上腺素（Iso）7-14天，建立可逆性肥大的小鼠模型。蛋白酶体抑制剂PS-519在Iso治疗的同时和之后递送。LVH通过心脏重量/体重比、组织学、经胸超声心动图和肥大基因表达进行定量。Iso治疗7天后，所有指标均显示LVH成功发展。另一组治疗7天，然后再观察7天。该组经历了ISO诱导的细胞大小、壁厚度和β-肌球蛋白重链表达的正常化。当同时给药时，PS-519在第7天预防了Iso诱导的LVH。此外，当在持续Iso给药的第二周期间对动物给予PS-519时，这些动物也通过几种措施经历了肥大消退。蛋白酶体抑制在预防LVH发展和促进LVH消退方面的成功，即使面对持续的肥大刺激，也证明了其作为治疗各种LVH相关心肌病患者的临床可及策略的潜在用途。
Current research in left ventricular hypertrophy (LVH) has largely focused on its progression and therapeutic mechanisms to prevent or slow its development. Few studies have centered on the regression or treatment of existing LVH. Nuclear factor-kappa B (NF-kappa B) is an inflammatory transcription factor that has been shown to be involved in LVH development. We hypothesized that proteasome-mediated NF-kappa B inhibition would prevent the development of LVH and promote its regression. A murine model of reversible hypertrophy was employed by administering isoproterenol (Iso) subcutaneously for 7-14 days. The proteasome inhibitor, PS-519, was delivered both concurrently and after Iso treatment. LVH was quantified by heart weight-to-body weight ratios, histology, transthoracic echocardiography, and hypertrophic gene expression. After 7 days of Iso treatment, all measures indicated successful development of LVH. Another group was treated for 7 days and then observed for an additional 7 days. This group experienced normalization of Iso-induced cell size, wall thickness, and beta-myosin heavy chain expression. When administered concurrently, PS-519 prevented Iso-induced LVH at 7 days. Furthermore, when PS-519 was given to animals during the second week of continued Iso treatment, these animals also experienced regression of hypertrophy by several measures. The success of proteasome inhibition in preventing LVH development and in promoting LVH regression, even in the face of continued hypertrophic stimulation, demonstrates its potential use as a clinically accessible strategy for treating patients with a variety of LVH-associated cardiomyopathies.