Retinoid X receptor agonists attenuates cardiomyopathy in streptozotocin-induced type 1 diabetes through LKB1-dependent anti-fibrosis effects
Retinoid X receptor agonists attenuates cardiomyopathy in streptozotocin-induced type 1 diabetes through LKB1-dependent anti-fibrosis effects
复制标题
类维生素A X 受体激动剂通过 LKB1 依赖性抗纤维化作用减轻链脲佐菌素诱导的心肌病 1 型糖尿病
DOI：
10.1042/cs20190985
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发表时间：
2020-03-01
期刊：
影响因子：
6
通讯作者：
Zeng, Jinzhang
中科院分区：
文献类型：
--
作者：
Chai, Dajun;Lin, Xiaoyan;Zeng, Jinzhang
糖尿病性心脏纤维化增加心室僵硬度，促进舒张功能障碍的发生。维甲酸X受体（Retinoid X receptor，RXR）在心脏发育中起重要作用，并与心血管疾病有关。在本研究中，我们研究了RXR激动剂治疗对链脲佐菌素（STZ）诱导的糖尿病心肌病（DCM）的影响及其机制。用RXR激动剂贝沙罗汀（Bex）或单独的载体处理由STZ注射诱导的Sprague-Dawley（SD）大鼠。进行超声心动图以确定心脏结构和功能。心脏成纤维细胞（CF）用高葡萄糖（HG）处理，有或没有指定浓度的Bex或RXR配体9-顺式-视黄酸（9-cis-RA）。测定沿着蛋白质丰度水平、胶原蛋白、体重（BW）、血液生化指标和转化生长因子-β（TGF-β）水平。检测了RXR α小干扰RNA（siRNA）对RXR α下调的影响。结果表明，贝沙罗汀治疗通过抑制心肌细胞凋亡和心肌纤维化改善左心室功能障碍。糖尿病大鼠心脏组织匀浆免疫印迹显示，贝沙罗汀激活肝激酶B1（LKB 1）信号，抑制p70核糖体蛋白S6激酶（p70 S6 K）。贝沙罗汀治疗可降低DCM大鼠心脏组织中增加的胶原水平。HG处理CFs导致LKB 1活性显著降低，p70 S6 K活性显著升高。RXR α介导9-cis-RA对HG诱导的LKB 1/p70 S6 K激活变化的拮抗作用。我们的研究结果表明，RXR激动剂通过调节LKB 1/p70 S6 K信号通路抑制心肌纤维化来改善STZ诱导的DCM。RXR激动剂可作为治疗DCM的新型治疗剂。
Diabetic cardiac fibrosis increases ventricular stiffness and facilitates the occurrence of diastolic dysfunction. Retinoid X receptor (RXR) plays an important role in cardiac development and has been implicated in cardiovascular diseases. In the present study, we investigated the effects of RXR agonist treatment on streptozotocin (STZ)-induced diabetic cardiomyopathy (DCM) and the underlying mechanism. Sprague-Dawley (SD) rats induced by STZ injection were treated with either RXR agonist bexarotene (Bex) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with high glucose (HG) with or without the indicated concentration of Bex or the RXR ligand 9-cis-retinoic acid (9-cis-RA). The protein abundance levels were measured along with collagen, body weight (BW), blood biochemical indexes and transforming growth factor-beta (TGF-beta) levels. The effects of RXR alpha down-regulation by RXR alpha small interfering RNA (siRNA) were examined. The results showed that bexarotene treatment resulted in amelioration of left ventricular dysfunction by inhibiting cardiomyocyte apoptosis and myocardial fibrosis. Immunoblot with heart tissue homogenates from diabetic rats revealed that bexarotene activated liver kinase B1 (LKB1) signaling and inhibited p70 ribosomal protein S6 kinase (p70S6K). The increased collagen levels in the heart tissues of DCM rats were reduced by bexarotene treatment. Treatment of CFs with HG resulted in significantly reduced LKB1 activity and increased p70S6K activity. RXR alpha mediated the antagonism of 9-cis-RA on HG-induced LKB1/p70S6K activation changes in vitro. Our findings suggest that RXR agonist ameliorates STZ-induced DCM by inhibiting myocardial fibrosis via modulation of the LKB1/p70S6K signaling pathway. RXR agonists may serve as novel therapeutic agents for the treatment of DCM.