Angiotensin II AT1 receptor blockade normalizes CD11b+ monocyte production in bone marrow of hypercholesterolemic monkeys
Introduction
The vascular infiltration of blood-borne monocytes induced by hypercholesterolemia is an obligatory early event in atherogenesis that is dependent on the adhesion of monocytes to endothelium. Sustained monocyte adhesion required for transendothelial migration of monocytes into the intima is a complex process requiring monocyte expression of integrins that include the β2 heterodimer variants CD11a/CD18, CD11b/CD18 and CD11c/CD18. Elevated monocyte expression of CD11b observed in patients with hypercholesterolemia is considered a indication of monocyte activation and heightened atherogenic potential given the positive correlation between CD11b expression and adhesion to endothelium [1]. The renin–angiotensin system (RAS) may play a role in this activation process since hypercholesterolemia upregulates AT1 receptor expression in a variety of tissues [2] and in vitro stimulation of AT1 subtype receptors by angiotensin (Ang) II directly increases monocyte CD11b [3]. The suppression of monocyte CD11b by AT1 receptor blockade in patients with coronary artery disease [4] and in monkeys with hypercholesterolemia-induced atherosclerosis [5] provides additional evidence that the RAS regulates the phenotype of circulating monocytes and their atherogenicity. The anti-inflammatory action of Ang II receptor blockers (ARBs) reflected by diminished CD11b expression may be an important mechanism by which this drug class exerts its anti-atherosclerotic effects independent of blood pressure-lowering. Nevertheless, it remains unclear how hypercholesterolemia shifts monocyte development into activated and pro-atherogenic phenotypes, whether AT1 receptors mediate these events, and at what stages of development ARBs exert their anti-inflammatory influence.
A recent study in hypercholesterolemic mice [6] demonstrated that the lack of AT1 receptors in donor bone marrow (BM) cells inhibited atherosclerotic lesion development despite intact recipient vascular AT1 receptors. These results signify the importance of BM cell AT1 receptors to the atherogenic process and are consistent with the earlier demonstration that BM AT1 receptors are necessary for normal monocyte development and tissue macrophage infiltration [7]. Hematopoietic stem cells (HSCs) identified by the surface glycoprotein CD34 are the origin of the majority of tissue macrophages found in atherosclerotic lesions [7]. Stimulation of CD34+ HSC AT1 receptors with Ang II preferentially enhances the production of myeloid progenitor cells in culture [8]. The dietary induction of hypercholesterolemia enhances BM myelopoiesis in animal models of atherosclerosis [9], [10] which may then facilitate atherogenesis by increasing production of pre-activated myeloid lineage inflammatory cells predisposed to participate in atherogenesis. The potential for hypercholesterolemia to increase AT1 receptor expression is reportedly a function of the response to elevated low density lipoprotein (LDL) concentrations [11] which may also be a mechanism whereby hypercholesterolemia aggravates hypertension. In clinical studies, the pressor response to Ang II infusion was related to LDL cholesterol concentration even in normocholesterolemic or mildly hypercholesterolemic patients [12]. The same concentration-dependent upregulation of vascular smooth muscle cell AT1 receptors by exposure to LDL and the enhanced proliferative response to subsequent Ang II stimulation [13] may also regulate Ang II-mediated effects on other cell types including HSCs. We proposed that a direct stimulatory effect of increased plasma LDL concentration on HSC AT1 receptor expression may explain the exaggerated myelopoiesis observed in experimental hypercholesterolemia. We evaluated this hypothesis by evaluating CD34+ HSC function in response to diet-induced hypercholesterolemia and systemic AT1 receptor blockade in a monkey model of atherosclerosis. To more directly determine the influence of LDL on the BM RAS, we also investigated the interaction between LDL receptor- and AT1 receptor-mediated HSC function.
Section snippets
Animals and experimental protocol
Fourteen adult, male cynomolgus (Macaca fascicularis) monkeys (average weight 4.86 ± 0.89 kg) imported from Indonesia were fed a commercial diet (Monkey Chow #5038, Purina Mills-LabDiet, St. Louis, MO) for 35 weeks to establish a normocholesterolemia (NC) baseline. Monkeys were then fed a high-cholesterol-diet (0.067 mg cholesterol/kJ) for an additional 36 weeks. Fifteen weeks after the induction of hypercholesterolemia (HC), monkeys were assigned to groups receiving a single daily subcutaneous
Effects of hypercholesterolemia and losartan on plasma and hemodynamic variables
Plasma TC, LDL-C, HDL-C, VLDL-C and Ang II concentrations and hemodynamic data at the NC baseline, HC baseline 15 weeks after dietary induction of HC, and at the end of treatment (TX) and post-treatment (Post-TX) periods are presented in Table 1. The induction of HC in monkeys preassigned to either vehicle or losartan treatments increased plasma TC, LDL-C, and VLDL-C concentrations (P < 0.05), but had no effect on plasma Ang II concentrations. Blood pressures and heart rates were also unaffected
Hypercholesterolemia simulates myelopoiesis and monocyte CD11b expression in monkeys
In the present study, monkeys provided a cholesterol-containing diet had increased numbers of BM MNCs and CD11b on both PB and BM monocytes. These results agree with results from other animal studies in which dietary hypercholesterolemia was associated with BM hypercellularity and increased monocytic precursor proliferative capacity [9], [10]. In the present study, the shift in CD34+ HSC function toward the production of CD11b+/CD14+ myeloid cells determined by in vitro assays paralleled the in
Acknowledgements
In addition to National Heart, Lung, and Blood Institute Grants HL-068258 and HL-051952 (to C.M. Ferrario) and American Heart Association Grant 0130405N (to W.B. Strawn), the authors gratefully acknowledge grant support in part provided by Unifi (Greensboro, NC), the Farley-Hudson Foundation (Jacksonville, NC), and Merck & Co., Inc.
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