Osteopontin Improves Cardiac Remodeling and Function After Myocardial Infarction
2Leviev Cardiovascular and Thoracic Center, Sheba Medical Center, Tel Hashomer, Israel
Introduction: The adult human heart, as opposed to the neonatal heart, has minimal capacity to regenerate, and any significant loss ultimately leads to heart failure. Both regenerative and repair processes in the heart depend on the macrophage`s function. Osteopontin (OPN) is a macrophage-secreted protein that correlates with heart failure in the adult heart. Nevertheless, the role of OPN in myocardial regeneration has never been studied.
Objective: To test the role of OPN in myocardial regeneration and repair.
Methods and results: The resection of the neonatal heart`s apex in mice showed that cardiac macrophages secreted high amounts of OPN during myocardial regeneration. Histological analysis showed that OPN K.O. mice had an impaired regenerative process compared to wild type mice. A scratch "wound healing” assay showed that OPN accelerated the gap closure in both neonatal cardiomyocytes and fibroblasts. OPN also stimulated tube formation in an angiogenesis assay. Echocardiography and Speckle-tracking strain imaging showed that a single injection of OPN into the infarcted heart of adult mice improved cardiac remodeling and function 30 days after myocardial infarction (MI). FACS results showed that OPN injection increased F4/80+CCR2- tissue-resident macrophages which considered reparative and pro-angiogenic. Finally, the morphometric analysis showed that OPN injection increased scar thickness, which in turn, led to a decrease in wall stress (Laplace law).
Conclusions: OPN improves cardiac remodeling and function after MI. Our findings could explain macrophages` essential role in myocardial regeneration and suggest a new strategy for heart repair after MI.