Retinoid X receptor agonists attenuates cardiomyopathy in streptozotocin-induced type 1 diabetes through LKB1-dependent anti-fibrosis effects
| Autor: | Qinyun Ruan, Jinzhang Zeng, Changsheng Xu, Hong Xie, Dajun Chai, Xiaoyan Lin, Jie Liu, Jinxiu Lin, Qiaowen Zheng |
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| Rok vydání: | 2019 |
| Předmět: |
Agonist
Male medicine.medical_specialty Cardiac fibrosis medicine.drug_class P70-S6 Kinase 1 Retinoid X receptor Protein Serine-Threonine Kinases Streptozocin Rats Sprague-Dawley AMP-Activated Protein Kinase Kinases Diabetic cardiomyopathy Internal medicine medicine Animals Humans Bexarotene Chemistry Ribosomal Protein S6 Kinases 70-kDa General Medicine medicine.disease Streptozotocin Fibrosis Rats Endocrinology Diabetes Mellitus Type 1 Retinoid X Receptors Myocardial fibrosis Cardiomyopathies medicine.drug |
| Zdroj: | Clinical science (London, England : 1979). 134(6) |
| ISSN: | 1470-8736 |
| Popis: | 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-β (TGF-β) levels. The effects of RXRα down-regulation by RXRα 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. RXRα 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. |
| Databáze: | OpenAIRE |
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