Bone marrow–derived MCP1 required for experimental aortic aneurysm formation and smooth muscle phenotypic modulation Christopher W. Moehle, MS, Castigliano.

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Bone marrow–derived MCP1 required for experimental aortic aneurysm formation and smooth muscle phenotypic modulation Christopher W. Moehle, MS, Castigliano M. Bhamidipati, DO, Matthew R. Alexander, MS, Gaurav S. Mehta, MBBS, James N. Irvine, BS, Morgan Salmon, PhD, Gilbert R. Upchurch, MD, Irving L. Kron, MD, Gary K. Owens, PhD, Gorav Ailawadi, MD The Journal of Thoracic and Cardiovascular Surgery Volume 142, Issue 6, Pages 1567-1574 (December 2011) DOI: 10.1016/j.jtcvs.2011.07.053 Copyright © 2011 Terms and Conditions

Figure 1 Monocyte chemotactic protein 1 (MCP1) is increased in abdominal aortic aneurysm (AAA) and required for disease progression. A, Immunohistochemistry performed 14 days after surgery indicates MCP1 is upregulated in elastase-perfused AAAs compared with saline-perfused controls. B, MCP1 more abundant in tissue from patients undergoing open aneurysm repair than in control aorta from patients undergoing coronary artery bypass grafting (CABG). Wild type (WT) aortas perfused with elastase (black squares) show significantly greater change in aortic diameter than MCP1KO aortas perfused with elastase (black triangles) at 14 days (P < .0001). C, MCP1KO aortas statistically indistinguishable from WT aortas perfused with saline (black diamonds). The Journal of Thoracic and Cardiovascular Surgery 2011 142, 1567-1574DOI: (10.1016/j.jtcvs.2011.07.053) Copyright © 2011 Terms and Conditions

Figure 2 MCP1KO reduces inflammation and protects from medial degredation. Immunohistochemistry performed 14 days after elastase perfusion indicated levels of Mac-2, interleukin-1β (IL-1β), and matrix metalloproteinase (MMP)9 are significantly reduced in MCP1KO aortas (left column) compared with WT aortas (right column) 14 days after elastase perfusion. A, Intact elastic fibers, as detected by Movat pentachrome stain (black), and SMαA-expressing cells (red) are increased in MCP1KO mice compared with WT mice. B, In contrast, medial cells of MCP1KO mice produce significantly less MMP2 (brown) as measured by immunostaining. The Journal of Thoracic and Cardiovascular Surgery 2011 142, 1567-1574DOI: (10.1016/j.jtcvs.2011.07.053) Copyright © 2011 Terms and Conditions

Figure 3 Mice lacking monocyte chemotactic protein 1 (MCP1) in bone marrow do not form aneurysms after elastase perfusion. Wild type (WT) mice with bone marrow cells (BMCs) donated from MCP1KO mice (MCP1KO→WT) showed significant reduction in aortic dilation 14 days after elastase perfusion compared with WT mice with BMCs donated from WT mice (WT→WT) or MCP1KO mice with BMCs donated from WT mice (WT→MCP1; P < .0001). MCP1KO→WT mice also showed significantly increased protection compared with mice with MCP1KO BMCs transplanted into MCP1KO recipients (P = .0088). The Journal of Thoracic and Cardiovascular Surgery 2011 142, 1567-1574DOI: (10.1016/j.jtcvs.2011.07.053) Copyright © 2011 Terms and Conditions

Figure 4 Knockout of monocyte chemotactic protein 1 (MCP1) in bone marrow cells (BMCs) decreases inflammatory markers and increases intact elastic fibers and SMαA expression. A, Immunohistochemistry performed 14 days after elastase perfusion indicates that expression of Mac2, matrix metalloproteinase (MMP)2, MMP9, and interleukin 1β (IL-1β) is markedly diminished in MCP1KO→WT mice. B, This correlates with a significant increase in elastic fibers (black) and SMαA-expressing cells. The Journal of Thoracic and Cardiovascular Surgery 2011 142, 1567-1574DOI: (10.1016/j.jtcvs.2011.07.053) Copyright © 2011 Terms and Conditions

Figure 5 Monocyte chemotactic protein 1 (MCP1) acts on cultured aortic smooth muscle cells (SMCs) to repress SMC marker genes and induce matrix metalloproteinases (MMPs). Cells treated with 0 to 50 ng/mL MCP1showed a dose-dependent increase in (A) MMP2 and (B) MMP9 and coordinate with a decrease in (C) smooth muscle myosin heavy chain (SM-MHC), (D) SM22α, and (E) SMαA. ∗P < .05. The Journal of Thoracic and Cardiovascular Surgery 2011 142, 1567-1574DOI: (10.1016/j.jtcvs.2011.07.053) Copyright © 2011 Terms and Conditions