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首页> 外文期刊>Life sciences >Rapamycin (sirolimus) protects against hypoxic damage in primary heart cultures via Na+/Ca2+ exchanger activation.
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Rapamycin (sirolimus) protects against hypoxic damage in primary heart cultures via Na+/Ca2+ exchanger activation.

机译：雷帕霉素（西罗莫司）可通过Na + / Ca2 +交换子激活来保护原代心脏培养物中的低氧损伤。

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AIMS: Rapamycin (sirolimus) is an antibiotic that inhibits protein synthesis through mammalian targeting of rapamycin (mTOR) signaling, and is used as an immunosuppressant in the treatment of organ rejection in transplant recipients. Rapamycin confers preconditioning-like protection against ischemic-reperfusion injury in isolated mouse heart cultures. Our aim was to further define the role of rapamycin in intracellular Ca(2+) homeostasis and to investigate the mechanism by which rapamycin protects cardiomyocytes from hypoxic damage. MAIN METHODS: We demonstrate here that rapamycin protects rat heart cultures from hypoxic-reoxygenation (H/R) damage, as revealed by assays of lactate dehydrogenase (LDH) and creatine kinase (CK) leakage to the medium, by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) measurements, and desmin immunostaining. As a result of hypoxia, intracellular calcium levels ([Ca(2+)](i)) were elevated. However, treatment of heart cultures with rapamycin during hypoxia attenuated the increase of [Ca(2+)](i). Rapamycin also attenuated (45)Ca(2+) uptake into the sarcoplasmic reticulum (SR) of skinned heart cultures in a dose- and time-dependent manner. KB-R7943, which inhibits the "reverse" mode of Na(+)/Ca(2+) exchanger (NCX), protected heart cultures from H/R damage with or without the addition of rapamycin. Rapamycin decreased [Ca(2+)](i) following its elevation by extracellular Ca(2+) ([Ca(2+)](o)) influx, thapsigargin treatment, or depolarization with KCl. KEY FINDINGS: We suggest that rapamycin induces cardioprotection against hypoxic/reoxygenation damage in primary heart cultures by stimulating NCX to extrude Ca(2+) outside the cardiomyocytes. SIGNIFICANCE: According to our findings, rapamycin preserves Ca(2+) homeostasis and prevents Ca(2+) overload via extrusion of Ca(2+) surplus outside the sarcolemma, thereby protecting the cells from hypoxic stress.
机译：目的：雷帕霉素（西罗莫司（Riromyus））是一种通过哺乳动物靶向雷帕霉素（mTOR）信号转导来抑制蛋白质合成的抗生素，并被用作免疫抑制剂，用于治疗移植受者的器官排斥反应。雷帕霉素可在离体小鼠心脏培养物中提供类似预处理的保护作用，以防止缺血再灌注损伤。我们的目标是进一步定义雷帕霉素在细胞内Ca（2+）稳态中的作用，并研究雷帕霉素保护心肌细胞免受缺氧性损伤的机制。主要方法：我们在这里证明雷帕霉素可保护大鼠心脏培养物免受缺氧-再加氧（H / R）的损害，如通过MTT对乳酸脱氢酶（LDH）和肌酸激酶（CK）泄漏至培养基的测定所揭示的（3- [ 4,5-二甲基噻唑-2-基] -2,5-二苯基溴化四氮唑）和结蛋白免疫染色。由于缺氧，细胞内钙水平（[Ca（2 +）]（i））升高。但是，在缺氧期间用雷帕霉素治疗心脏文化会减弱[Ca（2 +）]（i）的增加。雷帕霉素还以剂量和时间依赖性的方式减弱皮肤心脏培养物的肌质网（SR）对（45）Ca（2+）的吸收。 KB-R7943可以抑制Na（+）/ Ca（2+）交换剂（NCX）的“反向”模式，可保护心脏培养物免受添加或不添加雷帕霉素的H / R损害。雷帕霉素通过细胞外Ca（2+）（[Ca（2 +）]（o））大量涌入，thapsigargin处理或用KCl去极化降低了其[Ca（2 +）]（i）的表达。关键发现：我们建议雷帕霉素通过刺激NCX挤出心肌细胞外的Ca（2+）来诱导原代心脏培养物中抗缺氧/复氧损伤的心脏保护作用。意义：根据我们的发现，雷帕霉素可保持Ca（2+）稳态，并通过在肌膜外挤出多余的Ca（2+）防止Ca（2+）超负荷，从而保护细胞免受低氧应激。

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