TY - JOUR
T1 - Hypercholesterolemia impairs megakaryopoiesis and platelet production in scavenger receptor BI knockout mice
AU - Ouweneel, Amber B.
AU - Hoekstra, Menno
AU - van der Wel, Ezra J.
AU - Schaftenaar, Frank H.
AU - Snip, Olga S.C.
AU - Hassan, Jasmin
AU - Korporaal, Suzanne J.A.
AU - Van Eck, Miranda
N1 - Funding Information:
This work was funded by Leiden University , and in part supported by a VICI grant 91813603 from the Netherlands Organisation for Scientific Research and the Landsteiner Foundation for Blood Transfusion Research ( #0912F , S.J.A.K.). M.V.E is an Established Investigator of the Dutch Heart Foundation (grant number 2007T056 ).
Funding Information:
This work was funded by Leiden University, and in part supported by a VICI grant 91813603 from the Netherlands Organisation for Scientific Research and the Landsteiner Foundation for Blood Transfusion Research (#0912F, S.J.A.K.). M.V.E is an Established Investigator of the Dutch Heart Foundation (grant number 2007T056).
Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2019/3
Y1 - 2019/3
N2 - Background and aims: 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. Methods: In this study, we compared megakaryopoiesis and platelet production in SR-BI knockout and wild-type mice. Results: In 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. Conclusions: In 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.
AB - Background and aims: 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. Methods: In this study, we compared megakaryopoiesis and platelet production in SR-BI knockout and wild-type mice. Results: In 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. Conclusions: In 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.
KW - HDL
KW - Megakaryocytes
KW - Scavenger receptor BI
KW - Thrombopoiesis
UR - http://www.scopus.com/inward/record.url?scp=85054073694&partnerID=8YFLogxK
U2 - 10.1016/j.atherosclerosis.2018.09.019
DO - 10.1016/j.atherosclerosis.2018.09.019
M3 - Article
C2 - 30278990
AN - SCOPUS:85054073694
SN - 0021-9150
VL - 282
SP - 176
EP - 182
JO - Atherosclerosis
JF - Atherosclerosis
ER -