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

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 4

PDPN neutralization reduces infarct size and cell death and stimulates angiogenesis after MI.

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PDPN neutralization reduces infarct size and cell death and stimulates a...
(A) Thin cardiac sections of saline treatment (left panel), IgG control (middle panel), and PDPN-neutralizing Ab–treated (right panel) mouse hearts at 30 days after MI were labeled with Masson’s trichrome staining. Treated animals (A, right panel) displayed a smaller scar compared with the animals in both control groups (A, left and middle panels). Quantitative analysis of the cardiac scar size showed significant reduction in the infarct area in the treated animals compared with the controls (graph, A) (n = 5/group). Data are presented as mean ± SEM. *P < 0.05 IgG control versus treated and #P < 0.05 saline control versus treated. One-way ANOVA and Bonferroni’s post hoc test were performed among all groups. (B) Thin cardiac sections of saline control (left panel) and PDPN-neutralizing Ab–treated (right panel) mouse hearts at 30 days after MI were immunolabeled with CD31 (red), α-SMA (green), and nuclei (blue). The new vessel formation in the scar tissue of treated animals (B, right panel) was significantly enhanced compared with the controls (B, left panel), while α-SMA positivity was reduced in the treated animals (B, right panel, graph). *P < 0.05 control versus treated (n = 5/group). Student’s t test was performed between the groups. (C) Thin cardiac sections of saline-treated control (left panel) and PDPN-neutralizing Ab–treated (right panel) hearts at 30 days after MI were indirectly immunolabeled with LYVE-1 (red), fibronectin (green), and nuclei (blue). PDPN neutralization did not affect neolymphangiogenesis and reduced the fibronectin distribution along the scar.