Rosuvastatin and simvastatin attenuate cisplatin-induced cardiotoxicity via disruption of endoplasmic reticulum stress-mediated apoptotic death in rats: targeting ER-Chaperone GRP78 and Calpain-1 pathways
| Autor: | Dalia O. Saleh, Dina F. Mansour, Rasha E. Mostafa |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
GRP78
Simvastatin Programmed cell death Health Toxicology and Mutagenesis Apoptosis Calpain-1 010501 environmental sciences Pharmacology Toxicology medicine.disease_cause 01 natural sciences Rosuvastatin 03 medical and health sciences 0302 clinical medicine lcsh:RA1190-1270 medicine lcsh:Toxicology. Poisons 0105 earth and related environmental sciences Cardiotoxicity biology business.industry Regular Article Calpain biology.protein Unfolded protein response Cisplatin ER stress business 030217 neurology & neurosurgery Oxidative stress medicine.drug |
| Zdroj: | Toxicology Reports Toxicology Reports, Vol 7, Iss, Pp 1178-1186 (2020) |
| ISSN: | 2214-7500 |
| DOI: | 10.1016/j.toxrep.2020.08.026 |
| Popis: | Cisplatin (CP) is a powerful antineoplastic chemotherapeutic agent with broad-spectrum properties. Acute and cumulative cardiotoxicity are major limiting factors for CP therapy. Various pathogenic pathways have been suggested to CP-induced cardiotoxicity; oxidative damage, ER stress, and programmed cell death/apoptosis. The present study aimed to assess the signaling mechanisms related to the advantageous effects of rosuvastatin (RSV) and simvastatin (SMV) against CP-related cardiac ER stress dependent apoptotic death in rats. Acute cardiotoxicity was induced by a single dose of CP (10 mg/kg, i.p.) on the 10th day of the experiment. RSV (10 mg/ kg/day) and SMV (10 mg/kg/day) were orally administered for 15 days. CP-treated rats showed significant alterations in electrocardiographic recordings and elevation in serum cardiac function biomarkers; troponin T content, lactate dehydrogenase and creatine kinase-MB levels as well as boost in the cardiac oxidative stress biomarkers. In addition, CP exposure resulted in GRP78 induction; an ER stress and elevation marker at calpain-1 content as well as activation of activated caspase-3 (ACASP3) and caspase-12 were reflected on CP-triggered apoptosis evidenced by elevation in the Bax/Bcl-2 ratio. However, RSV and SMV administration mitigate those adverse CP effects. Statins administration prominently alleviated CP-induced cardiac abnormalities exerting improvement in the ECG pattern and cardiac enzyme biomarkers. Interestingly, statins; RSV and SMV, disrupted CP-induced ER stress and the consequent apoptotic cell death evidenced by downregulation of ER-chaperone GRP78, calpain-1, ACASP3 and caspase-12 as well as decline in the Bax/Bcl-2 ratio. From all the previous findings, it can be suggested that statins namely; RSV and SMV, play protective role against CP-induced cardiac injury by regulating ER stress-mediated apoptotic pathways. |
| Databáze: | OpenAIRE |
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