Plasminogen Regulates Cardiac Repair After Myocardial Infarction Through its Noncanonical Function in Stem Cell Homing to the Infarcted Heart

• Published in: Journal of the American College of Cardiology 2014-07, Vol.63 (25), p.2862-2872
• Main Authors: Gong, Yanqing, PhD, Zhao, Yujing, BS, Li, Ying, BS, Fan, Yi, MD, PhD, Hoover-Plow, Jane, PhD
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; BM-derived stem cells; Bone marrow; Bone Marrow Transplantation - methods; Cardiology; Cardiology. Vascular system; Cardiovascular; Coronary heart disease; CXCR4; Disease Models, Animal; Fibrinolytic Agents - therapeutic use; Heart; Heart attacks; Heart Failure - etiology; Heart Failure - prevention & control; Hematopoietic Stem Cell Mobilization - methods; Internal Medicine; Medical sciences; Mice; myocardial infarction; Myocardial Infarction - complications; Myocardial Infarction - physiopathology; Myocardial Infarction - therapy; Myocarditis. Cardiomyopathies; plasminogen; Plasminogen - therapeutic use; Stem cells; Studies; Transplants & implants
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2013.11.070

Objectives The purpose of this study was to investigate the role of plasminogen (Plg) in stem cell–mediated cardiac repair and regeneration after myocardial infarction (MI). Background An MI induces irreversible tissue damage, eventually leading to heart failure. Bone marrow (BM)–derived stem cells promote tissue repair and regeneration after MI. Thrombolytic treatment with Plg activators significantly improves the clinical outcome in MI by restoring cardiac perfusion. However, the role of Plg in stem cell–mediated cardiac repair remains unclear. Methods An MI was induced in Plg-deficient (Plg−/− ) and wild-type (Plg+/+ ) mice by ligation of the left anterior descending coronary artery. Stem cells were visualized by in vivo tracking of green fluorescent protein (GFP)-expressing BM cells after BM transplantation. Cardiac function, stem cell homing, and signaling pathways downstream of Plg were examined. Results Granulocyte colony-stimulating factor, a stem cell mobilizer, significantly promoted BM-derived stem cell (GFP+ c-kit+ cell) recruitment into the infarcted heart and stem cell–mediated cardiac repair in Plg+/+ mice. However, Plg deficiency markedly inhibited stem cell homing and cardiac repair, suggesting that Plg is critical for stem cell–mediated cardiac repair. Moreover, Plg regulated C-X-C chemokine receptor type 4 (CXCR4) expression in stem cells in vivo and in vitro through matrix metalloproteinase-9. Lentiviral reconstitution of CXCR4 expression in BM cells successfully rescued stem cell homing to the infarcted heart in Plg-deficient mice, indicating that CXCR4 has a critical role in Plg-mediated stem cell homing after MI. Conclusions These findings have identified a novel role for Plg in stem cell–mediated cardiac repair after MI. Thus, targeting Plg may offer a new therapeutic strategy for stem cell–mediated cardiac repair after MI.