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Podoplanin neutralization improves cardiac remodeling and function after myocardial infarction
Maria Cimini, Venkata Naga Srikanth Garikipati, Claudio de Lucia, Zhongjian Cheng, Chunlin Wang, May M. Truongcao, Anna Maria Lucchese, Rajika Roy, Cindy Benedict, David A. Goukassian, Walter J. Koch, Raj Kishore
Maria Cimini, Venkata Naga Srikanth Garikipati, Claudio de Lucia, Zhongjian Cheng, Chunlin Wang, May M. Truongcao, Anna Maria Lucchese, Rajika Roy, Cindy Benedict, David A. Goukassian, Walter J. Koch, Raj Kishore
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Research Article Cardiology Cell biology

Podoplanin neutralization improves cardiac remodeling and function after myocardial infarction

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Abstract

Podoplanin (PDPN), a small mucin-type transmembrane glycoprotein, has been recently shown to be expressed by lymphangiogenic, fibrogenic, and mesenchymal progenitor cells in the acutely and chronically infarcted myocardium. PDPN binds to a C-type lectin–like receptor 2 highly expressed by CD11bhi cells following inflammatory stimuli. Why PDPN expression appears only after organ injury is currently unknown. Here, we characterize the role of PDPN in different stages of myocardial repair after infarction and propose a PDPN-mediated mechanism in the resolution of post–myocardial infarction (MI) inflammatory response and cardiac repair. Neutralization of PDPN led to significant improvements in the left ventricular (LV) functions and scar composition in animals treated with PDPN-neutralizing antibody. The inhibition of the interaction between PDPN and C-type lectin–like receptor 2 expressing immune cells in the heart enhances the cardiac performance, regeneration, and angiogenesis after MI. Our data indicate that modulating the interaction between PDPN-positive cells with the immune cells after MI positively affects immune cell recruitment and may represent a novel therapeutic target to augment post-MI cardiac repair, regeneration, and function.

Authors

Maria Cimini, Venkata Naga Srikanth Garikipati, Claudio de Lucia, Zhongjian Cheng, Chunlin Wang, May M. Truongcao, Anna Maria Lucchese, Rajika Roy, Cindy Benedict, David A. Goukassian, Walter J. Koch, Raj Kishore

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Figure 6

PDPN neutralization inhibits monocyte activation in vivo.

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PDPN neutralization inhibits monocyte activation in vivo.
(A and B). Thi...
(A and B). Thin cardiac sections from infarcted mice 3 days after MI were immunolabeled for PDPN (red) and CD68 (A), CD163 (B) (green), and nuclei (blue). PDPN-positive cells do not express CD68 and CD163, whereas CD68+ and CD163+ cells do not express PDPN. (C) Thin cardiac sections from saline control and (D) PDPN-neutralizing Ab–treated infarcted mouse hearts at 3 days after MI were indirectly immunolabeled with CD163 (red), CD68 (green), and nuclei (blue). Scars of treated animals (D) were characterized by a higher number of CD163+ cells compared with the saline control animals where the majority of the monocyte/macrophage population expressed CD68 (C). Quantitative analysis of the distribution of CD68 (C, graph) and CD163+ (D, graph) cells was performed (n = 3/group). Data are presented as mean ± SEM. *P < 0.05 saline control versus treated. Student’s t test was performed for analysis of differences between the groups (45). Flow cytometry analysis of the total resident monocyte/macrophage population isolated from the heart 3 days after MI confirmed the histology data. Mice treated with PDPN-neutralizing Ab were characterized by a higher percentage of CD163+ (G) and CD206+ (H) cells compared with the untreated animals where the monocyte/macrophage population was highly positive for CD68 (F). The total number of monocyte/macrophage recruited in the saline control and treated hearts was similar (E). Data are presented as mean ± SEM. ***P < 0.001 control versus treated (n = 3–4/group). Student’s t test was performed between the groups.

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