Abstract 698: Increases Reticulated Platelets due to Enhanced Proliferation and Expansion of Bone Marrow Megakaryocyte Progenitors Accelerates Atherosclerosis in Diabetes
Diabetes (type 1 & 2) is a major risk factor for cardiovascular disease which represents the major cause of mortality in this group. Patients with diabetes present with reticulated thrombocytosis (increased immature platelets), which lower the efficacy of current anti-platelet therapies. We hypothesized that the reticulated thrombocytosis observed in people with diabetes plays an important role in atherogenesis. Thus, we investigated the mechanisms contributing to increased reticulated platelets in diabetes. Streptozotocin induced diabetic mice had significantly higher level (2-fold) of reticulated platelets. This was paralleled by an increase in the population of megakaryocyte progenitors (MkPs) and megakaryocytes in the bone marrow (BM). Diabetes caused an increase in circulating thrombopoietin (TPO) without altering the expression of the TPO receptor (c-MPL) on any of the BM progenitor cells or circulating platelets. TPO expression is generally upregulated by Kupffer cell derived interleukin-6 (IL-6). We found more Kupffer cells in the liver of diabetic mice which expressed higher levels of cell surface RAGE (Receptor for Advanced Glycated End-products) and produced more IL-6. Depletion of Kupffer cells using clodronate liposomes normalized the levels of total and reticulated platelets along with MkPs in the BM. Rage-/- BM transplantation (BMT) into mice that were then made diabetic were protected from diabetes-induced thrombocytosis and MkP expansion. Kupffer cells from diabetic Rage-/- BMT mice failed to express IL-6 and plasma TPO levels remained similar to the non-diabetic mice. IL-6-/- BMT mice were also protected from diabetes-induced thrombocytosis. Together, we identified a role for RAGE in the liver Kupffer cells of diabetic mice that triggers IL-6 expression, which in-turn promotes TPO production. TPO then enhances proliferation and expansion of MkPs in the BM, resulting in an increase in the abundance of reticulated platelets. Using BM from a genetic model (Bcl-xPlt20) of low platelets transplanted into Ldlr+/- mice we found that lower circulating platelets resulted in smaller atherosclerotic lesions. Our data suggests that increased platelet production contributes to accelerated atherogenesis in diabetes.
Author Disclosures: M.J. Kraakman: None. D. Dragoljevic: None. N.M.J. Hanssen: None. K. Jandeleit-Dahm: None. B.T. Kile: None. E. Josefsson: None. M.A. Febbraio: None. J.P.F. Chin-Dusting: None. M.E. Cooper: None. P.R. Nagareddy: None. I.J. Goldberg: None. A.J. Murphy: None.
- © 2015 by American Heart Association, Inc.