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

Abstract：

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.

journal_name

Atherosclerosis

journal_title

Atherosclerosis

authors

Ouweneel AB,Hoekstra M,van der Wel EJ,Schaftenaar FH,Snip OSC,Hassan J,Korporaal SJA,Van Eck M

doi

10.1016/j.atherosclerosis.2018.09.019

subject

Has Abstract

pub_date

2019-03-01 00:00:00

pages

176-182

eissn

0021-9150

issn

1879-1484

pii

S0021-9150(18)31392-3

journal_volume

282

pub_type

杂志文章

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