Monday, July 19, 2010

Cholesterol-retentive Leukocytes

Elevated white cells in the bloodstream (leukocytosis) was correlated with cardiovascular disease and atherosclerosis nearly a century ago but the cause remains unclear. Elevated high-density lipoprotein (HDL), in contrast, is correlated with protection from cardiovascular disease, in part because HDL carries cholesterol away from macrophages in atherosclerotic plaques. Here, Yvan-Charvet and colleagues report that leukocytosis develops in mice lacking the membrane proteins ABCA1 and ABCG1 that normally transport cholesterol out of macrophages to lipoproteins. These ABCA1/G1-deficient mice suffer a myeloproliferative disorder and display an expansion of particular blood-forming (hematopoietic) stem cells. Although lymphoid (B, T, NK cells) precursor cells were unchanged, myeloid precursor cells, which give rise to granulocytes, macrophages, etc, were doubled. Similar findings in MyD88-knockout mice ruled out innate inflammation as a cause of leukocytosis. Transplantation of bone marrow from ABCA1/G1 transporter-deficient mice into (apoA1-transgenic) mice with elevated HDL blocked or slowed the development of leukocytosis, myeloproliferation, the particular stem cell population, and atherosclerosis. The figure shows that elevated HDL in apoA1-tg mice protected against heart disease (Fig 4B, left side shows the entire hearts and, right side, tissue sections from hosts transplanted with ABCA1/G1-deficient bone marrow; upper panel: diseased heart from a normal recipient mouse showing leukocyte infiltration and, lower panel, healthy heart from a HDL-elevated recipient).

The authors state that “these results suggest that HDL suppresses the proliferation of myeloid progenitor cells by promoting cholesterol efflux”. Thus, these transporters (intrinsically) or elevated HDL (extrinsically) can regulate hematopoiesis and atherosclerosis. They also reported that stimulating ABCA1/G1 expression above normal levels using a transcriptional activator (TO901317) increased cholesterol efflux and suppressed myeloid cell proliferation, suggesting a new therapeutic rationale.

Statins, such as atorvastatin (Lipitor) and rosuvastatin (Crestor), were designed and are prescribed to reduce serum cholesterol, which is associated with cardiovascular disease. Surprisingly, statins were also found to be anti-inflammatory. Could these results help explain statins' anti-inflammatory effects?

Laurent Yvan-Charvet, Tamara Pagler, Emmanuel L. Gautier, Serine Avagyan, Read L. Siry, Seongah Han, Carrie L. Welch, Nan Wang, Gwendalyn J. Randolph, Hans W. Snoeck, Alan R. Tall, "ATP-Binding Cassette Transporters and HDL Suppress Hematopoietic Stem Cell Proliferation" Science 25 June 2010: Vol. 328. no. 5986, pp. 1689 - 1693

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