Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure
Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure
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DOI：
10.1152/ajpheart.00771.2012
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发表时间：
2013-08-01
影响因子：
4.8
通讯作者：
Bernstein, Daniel
中科院分区：
文献类型：
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作者：
Rajagopalan, Viswanathan;Zhao, Mingming;Bernstein, Daniel
泛素-蛋白酶体系统(UPS)的改变在左心室肥厚和衰竭中已被描述，尽管结果不一致。UPS在右室肥厚(RVH)和右室衰竭(RVF)中的作用尚不清楚。鉴于RV质量与RV后负荷应激相关的百分比增加更大，就像在许多先天性心脏病变中所存在的那样，我们假设UPS的改变可能在RVH/RVF中发挥重要作用。检测继发于肺动脉缩窄(PAC)的RVH/RVF小鼠右室UPS的表达和活性。用环孢霉素和MG132抑制蛋白酶体，用11S PA28α亚基过表达激活蛋白酶体。PAC小鼠出现右室出血(右室重量与体重之比增加109.3%)、右室扩张伴间隔移位、右室功能障碍和临床右室颤动。蛋白酶体功能(26Sβ(5)类糜蛋白酶活性)下降了26%(P<；0.05)。19S亚基Rpt5(P<；0.0001)、UCHL1脱泛素酶(P<；0.0001)和S-E3泛素连接酶(P<；0.01)的蛋白表达增加，多泛素化蛋白(P<；0.05)和游离泛素(P=0.05)的蛋白表达也增加。促凋亡的bax增加(P<；0.0001)，而抗凋亡的bcl2减少(P<；0.05)，使bax/bcl2的比值增加了6倍。蛋白酶体抑制不会加速RVF。然而，通过心脏特异的蛋白酶体过表达来增强蛋白酶体部分改善了存活率。蛋白酶体活性在RVH/RVF中降低，这与关键的UPS调节因子上调和促凋亡信号有关。蛋白酶体功能的增强部分减弱了RVF，提示UPS功能障碍参与了RVF的发生。
Alterations in the ubiquitin-proteasome system (UPS) have been described in left ventricular hypertrophy and failure, although results have been inconsistent. The role of the UPS in right ventricular (RV) hypertrophy (RVH) and RV failure (RVF) is unknown. Given the greater percent increase in RV mass associated with RV afterload stress, as present in many congenital heart lesions, we hypothesized that alterations in the UPS could play an important role in RVH/RVF. UPS expression and activity were measured in the RV from mice with RVH/RVF secondary to pulmonary artery constriction (PAC). Epoxomicin and MG132 were used to inhibit the proteasome, and overexpression of the 11S PA28 alpha subunit was used to activate the proteasome. PAC mice developed RVH (109.3% increase in RV weight to body weight), RV dilation with septal shift, RV dysfunction, and clinical RVF. Proteasomal function (26S beta(5) chymotrypsin-like activity) was decreased 26% (P < 0.05). Protein expression of 19S subunit Rpt5 (P < 0.05), UCHL1 deubiquitinase (P < 0.0001), and Smurf1 E3 ubiquitin ligase (P < 0.01) were increased, as were polyubiquitinated proteins (P < 0.05) and free-ubiquitins (P = 0.05). Pro-apoptotic Bax was increased (P < 0.0001), whereas anti-apoptotic Bcl-2 decreased (P < 0.05), resulting in a sixfold increase in the Bax/Bcl-2 ratio. Proteasomal inhibition did not accelerate RVF. However, proteasome enhancement by cardiac-specific proteasome overexpression partially improved survival. Proteasome activity is decreased in RVH/RVF, associated with upregulation of key UPS regulators and pro-apoptotic signaling. Enhancement of proteasome function partially attenuates RVF, suggesting that UPS dysfunction contributes to RVF.