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

Abstract

The enhanced production of monocytes expressing pro-inflammatory markers such as the integrin CD11b in patients with hypercholesterolemia may promote vascular inflammation and exacerbate atherogenesis. The objective of the present study was to determine whether hypercholesterolemia stimulates the production of CD11b + monocytes in bone marrow, and whether the renin-angiotensin system participates in this process and thus provides a target for therapeutic intervention. The dietary induction of hypercholesterolemia in adult male cynomolgus monkeys was accompanied by increased bone marrow cellularity and elevated peripheral blood and bone marrow monocyte CD11b expression. Isolated bone marrow CD34 + hematopoietic stem cells (HSCs) evaluated by in vitro functional assays exhibited enhanced myeloproliferative capacity and differentiation into CD11b + monocytes. Treatment of hypercholesterolemic monkeys with the angiotensin II AT 1 receptor blocker losartan for 15 weeks reduced bone marrow cellularity, suppressed peripheral blood and bone marrow monocyte CD11b expression, and normalized CD34 + cell function assays. All variables returned to pretreatment levels 6 weeks after discontinuation of losartan treatment. Hypercholesterolemia was associated with increased CD34 + cell AT 1 receptor expression and an exaggerated in vitro myeloproliferative response to angiotensin II stimulation that positively correlated to plasma LDL concentrations. In vitro exposure to native low-density lipoproteins (LDL) also increased CD34 + cell AT 1 receptor expression and the myeloproliferative response to angiotensin II stimulation in a dose-dependent and receptor-mediated manner. Our data provide support for a positive regulatory role of plasma LDL on AT 1 receptor-mediated HSC differentiation and the production of pro-atherogenic monocytes. LDL-regulated HSC function may explain in part hypercholesterolemia-induced inflammation as well as the anti-inflammatory and antiatherosclerotic effects of AT 1 receptor blockers.

Bone Marrow Angiotensin AT 1 Receptor Regulates Differentiation of Monocyte Lineage Progenitors From Hematopoietic Stem Cells

“…11 However, the relative contribution of the BM renin-angiotensin system to hypercholesterolemia-associated monocytosis has not been fully investigated. 12 In the present study, we focused on the action of the AT 1 receptor expressed in BM cells and studied whether (1) Ang II affects the differentiation/proliferation from BM stem cells into monocyte-lineage cells, and (2) hypercholesterolemiaassociated monocytosis contributes to the development of AT 1 -mediated atherosclerosis. Our results demonstrated for the first time that (1) Ang II promotes M-CSF-induced differentiation from hematopoietic stem cells (HSCs; c-Kit ϩ Sca-1 ϩ Lin Ϫ ) into monocyte-lineage cells through upregulation of the M-CSF receptor c-Fms, and that (2) TNF-␣ derived from BM CD45 Ϫ CD34 Ϫ stromal cells growthcontrolled by Ang II specifically regulates the c-Fms expression in promonocytes (CD11b high Ly-6G low ), thus leading to the increased numbers of circulating monocytes that modulate AT 1 -mediated proatherogenic activities.…”

“…11 However, the relative contribution of the BM renin-angiotensin system to hypercholesterolemia-associated monocytosis has not been fully investigated. 12 In the present study, we focused on the action of the AT 1 receptor expressed in BM cells and studied whether (1) Ang II affects the differentiation/proliferation from BM stem cells into monocyte-lineage cells, and (2) …”

A CCR2/CCR5 Antagonist Attenuates an Increase in Angiotensin II-Induced CD11b+ Monocytes from Atherogenic ApoE−/− Mice

“…Previous studies have shown that the regulation of CD11b on monocytes by Ang II is increased or unchanged. Treatment of hypercholesterolemic monkeys with the angiotensin type I receptor antagonist losartan for 15 weeks suppressed peripheral blood and bone marrow monocyte CD11b expression [40]. Circulating monocytes from hypertensive patients showed an increased monocyte adhesion to endothelial cells and an increased expression of CD11b.…”

Role of Mineralocorticoid Receptor Antagonists in Cardiovascular Disease

“…The finding that Ang II functions as an obligatory mediator pathway for the formation of aortic fatty streaks in the presence of hypercholesterolemia and no changes in arterial pressure was first demonstrated in monkeys 36 . These findings led to the hypothesis that the RAAS is a critical contributor to the pathogenesis of atherosclerosis through stimulation of oxidative stress, inflammatory cytokines, and recruitment of monocytes into the subendothelial vascular spaces 36–39 . Proatherogenic aldosterone mechanism occurs via induction of oxidative stress, endothelial dysfunction, activation of adhesion molecules, and up-regulation of ACE and AT 1 receptors (see 27 for review).…”