Statins Inhibit Store-Operated Ca2+ Channels in a Dose Dependent Manner

Abstract

Background: In this study, it was aimed to examine the effects of statins on the Store-Operated Ca2+ Entry (SOCE) mechanism, which has an important role in the regulation of intracellular Ca2+. Materials and Methods: SOCE measurements were performed using RBL-1 cell lines. Cells loaded with Fura-2 were incubated with thapsigargin to empty the intracellular Ca2+ stores, and then Ca2+ was added to the bath solution to measure SOCE utilizing fluorescent microscope. For the test group, cells were pretreated with the desired compound concentration for 15 minutes prior to the initiation of Ca2+imaging. Ca2+ imaging was performed using rate-metric (Fura-2-based) Ca2+ imaging technique. Results: All statins except pitavastatin were found to have a statistically significant suppressive role on SOCE. It was found that mevastatin and atorvastatin, especially at 3 µM concentrations, were more effective on SOCE than all other statins. At high concentrations, metavastatin was found to suppress SOCE by more than 80%. The IC50 value for mevastatin was calculated as 4.76 µM. Conclusions: According to the findings obtained from this study, it was determined that statins, which are used as cholesterol lowering in the treatment of cardiovascular diseases, are effective on store-operated Ca2+ channels. It is believed that these effects of statins on SOCE, which were demonstrated for the first time in this study, may provide great benefits in understanding the role of statins in Ca2+ regulation and in developing new treatment methods. Key Words: SOCE, Orai1, Statins, Ca2+ Regulation

Keywords

• SOCE
• Orai1
• Statinler
• Ca2+ Regülasyonu

Project Number

1059B141800131

Statinler Doz Bağımlı Olarak Depo-Bağımlı Ca2+ Girişini Baskılar

Abstract

Amaç: Bu çalışmada statinlerin hücre içi Ca2+ regülasyonunda önemli bir role sahip olan SOCE mekanizması üzerine olan etkilerinin incelenmesi amaçlandı. Materyal ve metod: SOCE ölçümleri RBL-1 hücre hatları kullanılarak gerçekleştirildi. Fura-2 ile yüklenen hücreler thapsigargin ile inkübe edilerek hücre içi Ca2+ depolarının boşalması sağlandı ve sonrasında Ca2+ eklenerek SOCE ölçümleri floresan mikroskop kullanılarak gerçekleştirildi. Test grubu için hücreler, Ca2+ görüntülemenin başlamasından önce 15 dakika süreyle istenen bileşik konsantrasyonuyla ön işleme tabi tutuldu. Ca2+ görüntüleme oran-metrik (Fura-2 tabanlı) Ca2+ görüntüleme tekniği kullanılarak gerçekleştirildi. Bulgular: Pitavastatin haricinden diğer tüm statinlerin SOCE üzerinde istatistiksel olarak anlamlı ölçüde baskılayıcı rolü olduğu bulundu. Özellikle 3 µM konsantrasyonda mevastatin ve atorvastatinin diğer tüm statinlerden SOCE üzerinde daha etkin olduğu anlaşıldı. Yüksek konsantrasyonlarda ise metavastatinin %80 oranından fazla SOCE’yi baskıladığı bulundu. Mevastatin için IC50 değeri 4,76 µM olarak hesaplandı. Sonuç: Bu çalışmadan elde edilen bulgulara göre kardiyovasküler hastalıkların tedavisinde kolesterol düşürücü olarak kullanılan statinlerin sadece voltaj kapılı kanallar üzerinden değil ayrıca depo-bağımlı Ca2+ kanalları üzerinde etkin olduğu saptandı. Statinlerin SOCE üzerindeki bu etkileri, statinlerin Ca2+ regülasyonundaki rolünün anlaşılmasında ve yeni tedavi metotlarının geliştirilmesi açısından büyük faydalar sağlayabileceğine inanılmaktadır.

Keywords

• SOCE
• Orai1
• Statinler
• Ca2+ Regülasyonu

Supporting Institution

TÜBİTAK

Project Number

1059B141800131

Thanks

Bu çalışmada kullanılan RBL-1 hücre hattını temin eden Cambridge Üniversitesi Farmakolji Anabilim Dalı Öğretim Üyesi Dr. Taufiq Rahman’a teşekkür ederim.

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