Loss of Macrophage Wnt Secretion Improves Remodeling and Function after Myocardial Infarction in Mice - The 64th Annual Conference of the Israel Heart Society & The Israel Society of Cardiothoracic Surgery, 25-26 April 2017

Dahlia Palevski ^1,2 La-Paz Levin-Kotler ^1,2 David Kain ^1,2 Nili Naftali-Shani ^1,2 Natalie Landa ^1,2 Tammy Ben-Mordechai ^1,2 Tal Konfino ^1,2 Natali Molotski ^1,2 Rina Rosin-Arbesfeld ³ Richard A Lang ⁴ Jonathan Leor ^1,2

¹Neufeld Cardiac Research Institute, Sackler Faculty of Medicine, Tel Aviv University
²Tamman Cardiovascular Research Institute, Leviev Heart Center, Sheba Medical Center
³Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University
⁴The Visual Systems Group Divisions of Pediatric Ophthalmology and Developmental Biology, Cincinnati Children's Hospital Medical Center Research Foundation

Background:
Macrophages and Wnt proteins (Wnts) are independently involved in cardiac development, response to cardiac injury, and repair. However, the role of macrophage-derived Wnts in the healing and repair of myocardial infarction (MI) is unknown. Therefore, we sought to determine the role of macrophage Wnt signaling in infarct repair.

Methods and Results:
We show that the Wnt pathway is activated after MI in mice. Furthermore, we demonstrate that isolated infarct macrophages express distinct Wnt pathway components, compared with sham operation macrophages, and are a source of non-canonical Wnt ligands after MI. To determine the role of macrophage-derived Wnts in cardiac repair, we evaluated mice that lack the essential Wnt transporter Wntless (Wls) in macrophages, using a conditional cre-lox transgenic strategy. Significantly, Wls-deficient macrophages presented a unique subset of M2-like macrophages with anti-inflammatory, reparative and angiogenic properties as assessed by flow cytometry, genetic, cytokine and tube formation assays. Next, mice with macrophage-Wls deficiency and their controls underwent MI by left anterior descending coronary artery ligation. Serial echocardiography studies revealed that mice lacking macrophage Wnt secretion had improved left ventricular function and less adverse remodeling, compared with controls, 30 days after MI. Finally, mice lacking macrophage-Wls developed increased vascularization at the infarct border zone, 30 days after MI.

Conclusion:
We show, for the first time, that macrophage-derived Wnts are implicated in adverse cardiac remodeling and dysfunction after MI. Inhibiting macrophage Wnt secretion improves cardiac function, attenuates remodeling and increases angiogenesis after MI in mice. Together, macrophage Wnts could be a novel therapeutic target in infarct healing and repair.