title: Macrophages play a unique role in the plaque calcification by enhancing the osteogenic signals exerted by vascular smooth muscle cells.
abstract: Vascular calcification is a major risk factor for the cardiovascular disease, yet its underlying molecular mechanisms remain to be elucidated. Recently, we identified that osteogenic signals via bone morphogenetic protein (BMP)-2 exerted by vascular smooth muscle cells (VSMCs) play a crucial role in the formation of atherosclerotic plaque calcification. Here we report a synergistic interaction between macrophages and VSMCs with respect to plaque calcification. Treatment with conditioned medium (CM) of macrophages dramatically enhanced BMP-2 expression in VSMCs, while it substantially reduced the expression of matrix Gla-protein (MGP) that inhibits the BMP-2 osteogenic signaling. As a result, macrophages significantly accelerated the osteoblastic differentiation of C2C12 cells induced by VSMC-CM. In contrast, macrophage-CM did not enhance the osteoblastic gene expressions in VSMCs, indicating that macrophages unlikely induced the osteoblastic trans-differentiation of VSMCs. We then examined the effect of recombinant TNF-α and IL-1β on the VSMC-derived osteogenic signals. Similar to the macrophage-CM, both cytokines enhanced BMP-2 expression and reduced MGP expression in VSMCs. Nevertheless, only the neutralization of TNF-α but not IL-1β attenuated the effect of macrophage-CM on the expression of these genes in VSMCs, due to the very low concentration of IL-1β in the macrophage-CM. On the other hand, VSMCs significantly enhanced IL-1β expression in macrophages, which might in turn accelerate the VSMC-mediated osteogenic signals. Together, we identified a unique role of macrophages in the formation of plaque calcification in coordination with VSMCs. This interaction between macrophages and VSMCs is a potential therapeutic target to treat and prevent the atherosclerotic plaque calcification.
authors: Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto 602-8566, Japan. ikedak@koto.kpu-m.ac.jp
authors: Koji
authors: K
authors: Ikeda
authors: Yuka
authors: Y
authors: Souma
authors: Yoshiki
authors: Y
authors: Akakabe
authors: Youhei
authors: Y
authors: Kitamura
authors: Kiyonari
authors: K
authors: Matsuo
authors: Yoshiaki
authors: Y
authors: Shimoda
authors: Tomomi
authors: T
authors: Ueyama
authors: Satoaki
authors: S
authors: Matoba
authors: Hiroyuki
authors: H
authors: Yamada
authors: Mitsuhiko
authors: M
authors: Okigaki
authors: Hiroaki
authors: H
authors: Matsubara
mesh_terms: D055396:Bone Morphogenetic Protein 2 / Q000096:biosynthesis; D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000276:immunology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000276:immunology*; D010006:Osteoblasts / Q000276:immunology; D010012:Osteogenesis / Q000276:immunology*; D058226:Plaque, Atherosclerotic / Q000276:immunology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D061205:Vascular Calcification / Q000188:drug therapy / Q000276:immunology*; D000097568:Matrix Gla Protein
chemical_list: D055396:Bone Morphogenetic Protein 2; D002135:Calcium-Binding Proteins; D017077:Culture Media, Conditioned; D016326:Extracellular Matrix Proteins; D053583:Interleukin-1beta; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000097568:Matrix Gla Protein; C525718:BMP2 protein, human