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Angiotensin II AT1 receptor blockade normalizes CD11b+ monocyte production in bone marrow of hypercholesterolemic

William B Strawn1, Carlos M Ferrario

  • 1Hypertension and Vascular Research Center, Wake Forest University Health Sciences, Winston-Salem, NC 27157, United States. bstrawn@wfubmc.edu

Atherosclerosis
|August 19, 2007
PubMed

Insights

High cholesterol increases pro-inflammatory monocytes via stem cell changes. Blocking the angiotensin II AT(1) receptor with losartan normalizes this process, offering a potential therapeutic strategy for vascular inflammation.

Area of Science:

  • Cardiovascular Biology
  • Hematology
  • Pharmacology

Background:

  • Hypercholesterolemia is linked to increased pro-inflammatory monocytes (CD11b+), potentially driving vascular inflammation and atherosclerosis.
  • The role of the renin-angiotensin system in hypercholesterolemia-induced monocyte production and its therapeutic potential require investigation.

Purpose of the Study:

  • To investigate if hypercholesterolemia stimulates CD11b+ monocyte production in bone marrow.
  • To determine the involvement of the renin-angiotensin system in this process.
  • To explore angiotensin II AT(1) receptor blockers as a therapeutic intervention.

Main Methods:

  • Dietary induction of hypercholesterolemia in cynomolgus monkeys.
  • Analysis of bone marrow cellularity and CD11b expression on monocytes.
  • In vitro functional assays of CD34+ hematopoietic stem cells (HSCs).
  • Treatment with losartan (an AT(1) receptor blocker) and subsequent assessment of variables.

Main Results:

  • Hypercholesterolemia increased bone marrow cellularity and CD11b expression on monocytes.
  • HSCs showed enhanced myeloproliferative capacity and differentiation into CD11b+ monocytes.
  • Losartan treatment reduced cellularity, suppressed CD11b expression, and normalized HSC function.
  • Increased AT(1) receptor expression on HSCs correlated with LDL levels and angiotensin II response.
  • In vitro LDL exposure dose-dependently increased AT(1) receptor expression and HSC response to angiotensin II.

Conclusions:

  • Plasma LDL positively regulates HSC differentiation and pro-atherogenic monocyte production via the AT(1) receptor.
  • LDL-mediated HSC dysfunction contributes to hypercholesterolemia-induced inflammation.
  • AT(1) receptor blockers demonstrate anti-inflammatory and anti-atherosclerotic effects by targeting this pathway.

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