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mTOR Inhibition improves anaemia and reduces organ damage in a murine model of sickle cell disease
Author(s) -
Wang Jintao,
Tran Jennifer,
Wang Hui,
Guo Chiao,
Harro David,
Campbell Andrew D.,
Eitzman Daniel T.
Publication year - 2016
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.14057
Subject(s) - sirolimus , mtorc1 , medicine , erythropoiesis , spleen , pi3k/akt/mtor pathway , hydroxycarbamide , anemia , mechanistic target of rapamycin , pharmacology , endocrinology , disease , immunology , biology , apoptosis , biochemistry
Mechanistic target of rapamycin ( mTOR ) has been shown to play an important role in red blood cell physiology, with inhibition of mTOR signalling leading to alterations in erythropoiesis. To determine if mTOR inhibition would improve anaemia in sickle cell disease ( SCD ), mice with SCD were treated with the dual mTORC 1/2 inhibitor, INK 128. One week after daily oral drug treatment, erythrocyte count, haemoglobin, and haematocrit were all significantly increased while reticulocyte counts were reduced. These parameters remained stable during 3 weeks of treatment. Similar effects were observed following oral treatment with the mTORC 1 inhibitor, sirolimus. Sirolimus treatment prolonged the lifespan of sickle cell erythrocytes in circulation, reduced spleen size, and reduced renal and hepatic iron accumulation in SCD mice. Following middle cerebral artery occlusion, stroke size was reduced in SCD mice treated with sirolimus. In conclusion, mTOR inhibition is protective against anaemia and organ damage in a murine model of SCD.