Genetic ablation and pharmacological inhibition of immunosubunit β5i attenuates cardiac remodeling in deoxycorticosterone-acetate (DOCA)-salt hypertensive mice
Genetic ablation and pharmacological inhibition of immunosubunit β5i attenuates cardiac remodeling in deoxycorticosterone-acetate (DOCA)-salt hypertensive mice
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免疫亚基 beta5i 的基因消融和药理学抑制可减轻脱氧皮质酮醋酸盐 (DOCA) 高血压小鼠的心脏重塑。
DOI：
10.1016/j.yjmcc.2019.09.010
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发表时间：
2019-12-01
影响因子：
5
通讯作者：
Li, Hui-Hua
中科院分区：
文献类型：
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作者：
Cao, Hua-Jun;Fang, Jiao;Li, Hui-Hua
高血压性心脏重构是心力衰竭的主要原因。免疫蛋白酶体是蛋白酶体的诱导形式，其催化亚基β 5i（也称为LMP 7）参与血管紧张素II诱导的房颤;然而，其在脱氧皮质酮醋酸盐（DOCA）诱导的心脏重塑中的作用仍不清楚。对C57 BL/6 J野生型（WT）和β 5i敲除（β 5i KO）小鼠进行单肾切除术（假手术）和DOCA-盐处理三周。通过超声心动图和组织学分析评估心脏功能、纤维化和炎症。通过定量实时PCR和免疫印迹分析蛋白质和基因表达水平。我们的结果显示，DOCA-盐处理21天后，与假手术对照组相比，心脏中β 5i表达和糜蛋白酶样活性是最显著增加的因素。此外，DOCA盐诱导的血压升高、不良心脏功能、心室和肌细胞肥大、间质纤维化、氧化应激和炎症在β 5i KO小鼠中显著减弱。这些发现在β 5i抑制剂PR-957处理的小鼠中得到了验证。此外，阻断PTEN（在染色体10上缺失的磷酸盐和张力蛋白同源物的基因）显著减弱了β 5i敲除对DOCA-盐诱导的心脏重构的抑制作用。DOCA-盐应激上调β 5 i的表达，促进了PTEN的降解和下游信号（AKT/mTOR、TGF-β 1/Smad 2/3、NOX和NF-κ B B）的激活，最终导致心脏肥大性重塑。本研究为β 5i通过调节PTEN稳定性在DOCA盐诱导的心脏重构中发挥关键作用提供了新的证据，并表明β 5i的抑制可能是治疗高血压心脏病的有希望的治疗靶点。
Hypertensive cardiac remodeling is a major cause of heart failure. The immunoproteasome is an inducible form of the proteasome and its catalytic subunit beta 5i (also named LMP7) is involved in angiotensin II-induced atrial fibrillation; however, its role in deoxycorticosterone-acetate (DOCA)-salt-induced cardiac remodeling remains unclear. C57BL/6 J wild-type (WT) and beta 5i knockout (beta 5i KO) mice were subjected to uninephrectomy (sham) and DOCA-salt treatment for three weeks. Cardiac function, fibrosis, and inflammation were evaluated by echocardiography and histological analysis. Protein and gene expression levels were analyzed by quantitative real-time PCR and immunoblotting. Our results showed that after 21 days of DOCA-salt treatment, beta 5i expression and chymotrypsin-like activity were the most significantly increased factors in the heart compared with the sham control. Moreover, DOCA-salt-induced elevation of blood pressure, adverse cardiac function, chamber and myocyte hypertrophy, interstitial fibrosis, oxidative stress, and inflammation were markedly attenuated in beta 5i KO mice. These findings were verified in beta 5i inhibitor PR-957-treated mice. Moreover, blocking of PTEN (the gene of phosphate and tensin homolog deleted on chromosome ten) markedly attenuated the inhibitory effect of beta 5i knockout on DOCA-salt-induced cardiac remodeling. Mechanistically, DOCA-salt stress upregulated the expression of beta 5i, which promoted the degradation of PTEN and the activation of downstream signals (AKT/mTOR, TGF-beta 1/Smad2/3, NOX, and NF-kappa B), which ultimately led to cardiac hypertrophic remodeling. This study provides new evidence of the critical role of beta 5i in DOCA-salt-induced cardiac remodeling through the regulation of PTEN stability, and indicates that the inhibition of beta 5i may be a promising therapeutic target for the treatment of hypertensive heart diseases.