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Ouweneel, A.B.; Hoekstra, M.; Wel, E.J. van der; Schaftenaar, F.H.; Snip, O.S.C.; Hassan, J.; ... ; Eck, M. van (2018)

Hypercholesterolemia impairs megakaryopoiesis and platelet production in scavenger receptor BI knockout mice

Article / Letter to editor
Thrombocytopenia in scavenger receptor BI (SR-BI) knockout mice is suggested to result from augmented platelet clearance induced by elevated intracellular unesterified cholesterol (UC) levels. We hypothesize that SR-BI deficiency may also influence platelet production at the level of its precursor cell in the bone marrow, the megakaryocyte.\nIn this study, we compared megakaryopoiesis and platelet production in SR-BI knockout and wild-type mice.\nIn line with our hypothesis, megakaryocytes from SR-BI knockout mice exhibited UC accumulation while no accumulation of UC was detectable in wild-type megakaryocytes. Bone marrow expression of transcription factors involved in megakaryocyte maturation was induced, but megakaryocyte counts were unchanged in bone marrow of SR-BI knockout mice. Interestingly, we did find a striking 62% decrease (p < 0.01) in proplatelet production by SR-BI knockout megakaryocytes. SR-BI knockout mice displayed an impaired increase in circulating platelet...Show moreThrombocytopenia in scavenger receptor BI (SR-BI) knockout mice is suggested to result from augmented platelet clearance induced by elevated intracellular unesterified cholesterol (UC) levels. We hypothesize that SR-BI deficiency may also influence platelet production at the level of its precursor cell in the bone marrow, the megakaryocyte.\nIn this study, we compared megakaryopoiesis and platelet production in SR-BI knockout and wild-type mice.\nIn line with our hypothesis, megakaryocytes from SR-BI knockout mice exhibited UC accumulation while no accumulation of UC was detectable in wild-type megakaryocytes. Bone marrow expression of transcription factors involved in megakaryocyte maturation was induced, but megakaryocyte counts were unchanged in bone marrow of SR-BI knockout mice. Interestingly, we did find a striking 62% decrease (p < 0.01) in proplatelet production by SR-BI knockout megakaryocytes. SR-BI knockout mice displayed an impaired increase in circulating platelet concentrations and bone marrow megakaryocyte numbers upon thrombopoietin challenge. Importantly, megakaryocytes from normolipidemic bone marrow-specific SR-BI knockout mice exhibited a normal ability to produce proplatelets. Moreover, bone marrow-specific deletion of SR-BI did not impair the thrombopoietin response or induce thrombocytopenia, confirming that absence of megakaryocyte SR-BI does not underlie the thrombocytopenic phenotype in total body SR-BI knockout mice.\nIn conclusion, the elevation of plasma unesterified cholesterol levels impairs megakaryopoiesis and platelet production in SR-BI knockout mice. Our findings suggest that, in addition to an increased platelet clearance, a decrease in platelet production may also, in part, explain the thrombocytopenic phenotype associated with SR-BI deficiency in mice.Show less
Scavenger receptor BI
HDL
Megakaryocytes
Thrombopoiesis
All authors
Ouweneel, A.B.; Hoekstra, M.; Wel, E.J. van der; Schaftenaar, F.H.; Snip, O.S.C.; Hassan, J.; Korporaal, S.J.A.; Eck, M. van
Date
2018-09-22
Volume
282
Pages
176 - 182
DOI
doi:10.1016/j.atherosclerosis.2018.09.019