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 5

PDPN neutralization enhances endogenous tissue regeneration after MI.

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PDPN neutralization enhances endogenous tissue regeneration after MI. (A...
(A) Thin cardiac sections of saline control and PDPN-neutralizing Ab–treated mouse hearts at 7 days after MI were indirectly immunolabeled with NKX-2.5 (red) and nuclei (blue). The ischemic heart tissue of animals treated with PDPN-neutralizing Ab was characterized by a significantly higher number of NKX-2.5–expressing cells (A, right panel) compared with the untreated group (A, left panel). (B) Thin cardiac sections of saline control and PDPN-neutralizing Ab–treated mouse hearts at 7 days after MI were indirectly immunolabeled with NKX-2.5 (red), troponin T (green), and nuclei (blue). The NKX-2.5–positive cells were found dispersed at the BZ of the MI or organized in groups of cells, resembling niches. All NKX-2.5–positive cells were also positive for troponin T (B, right panel). Some NKX-2.5–positive cells were also present in the scar/BZ of the untreated animals but none expressed troponin T (B, left panel) (n = 3/group). In order to correlate the NKX-2.5–positive small myocytes seen in the treated animals at 7 days after MI, we immunolabeled (C–E) thin cardiac sections of PDPN-neutralizing Ab–treated mouse hearts at 30 days after MI with connexin 43 (C) (red), troponin T (D) (red), troponin I (E) (red), α-SARC actin (green) (C–E), and (nuclei) blue. The scar of animals treated with PDPN Ab (C–E) was characterized by islets of small myocytes expressing these myocyte markers (C–E) (n = 5/group).