Macrophage Depletion by Clodronate Attenuates Bone Morphogenetic Protein-7 Induced M2 Macrophage Differentiation and Improved Systolic Blood Velocity in Atherosclerosis

Overview

Journal Transl Res

Publisher Elsevier

Specialty Pathology

Date 2018 Aug 15

PMID 30107156

Citations 13

Authors

Heidi Shoulders

Kaley H Garner

Dinender K Singla

Affiliations

Soon will be listed here.

Abstract

Bone morphogenetic protein-7 (BMP-7) affects the presence of macrophage subtypes in vitro and in vivo at an early stage of atherosclerosis (ATH); however, it remains unknown whether BMP-7 treatment affects the development and progression of ATH at a mid-stage of the disease. We therefore performed a Day 28 (D28) study to examine BMP-7's potential to affect monocyte differentiation. Atherosclerosis was developed in ApoE KO mice, and these animals were treated with intravenous injections of BMP-7 and/or liposomal clodronate (LC). BMP-7 significantly (P < 0.05) lowers plaque formation following induction of atherosclerosis. However, upon macrophage depletion, BMP-7 fails to significantly alter plaque progression suggesting a direct role of BMP-7 on macrophages. Immunohistochemical staining of carotid arteries was performed to determine BMP-7's effect on pro-inflammatory M1 inducible nitric oxide synthase and anti-inflammatory M2 (cluster of differentiation [CD]206, Arginase-1) macrophages, and monocytes ( CD14). BMP-7 significantly reduced pro-inflammatory M1 macrophages and increased anti-inflammatory M2 macrophages at D28, while BMP-7 showed no effect on M2 macrophage differentiation in animals treated with LC. Enzyme-linked immunosorbent assay data showed significant reduction in proinflammatory cytokines (Interleukin-6 [IL-6]), monocyte chemoattractant protein-1, and tumor necrosis factor-α) and a significant increase in anti-inflammatory cytokine (IL-10) in BMP-7 treated mice (P < 0.05).Western blot analysis of arterial tissue confirms a significant increase in pro-survival kinases extracellular-signal regulated kinase and SMAD and a reduction in pro-inflammatory kinases p38 and c-Jun N-terminal kinase in BMP-7 treated mice (P < 0.05). Overall, this study suggests that clodronate treatment inhibits BMP-7 induced differentiation of monocytes into M2 macrophages and improved systolic blood velocity.

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