BMP Antagonist Gremlin 2 Limits Inflammation After Myocardial Infarction
| Autor: | Kristof Nolan, Amrita Mukherjee, Sergey Ryzhov, John A. Schoenhard, Richard J. Gumina, Antonis K. Hatzopoulos, Mohamed A. Saleh, David G. Harrison, Lehanna N. Sanders, Thomas B. Thompson, William G. McMaster, Mark A. Magnuson |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Cardiac function curve Pathology medicine.medical_specialty Mice 129 Strain Physiology Myocardial Infarction Bone Morphogenetic Protein 2 Mice Transgenic Inflammation Bone morphogenetic protein Bone morphogenetic protein 2 Article Mice 03 medical and health sciences medicine Animals Humans Myocyte Myocytes Cardiac Myocardial infarction Cells Cultured Mice Knockout business.industry Endothelial Cells Proteins medicine.disease Mice Inbred C57BL 030104 developmental biology Quinolines Cancer research Cytokines Pyrazoles Female Tumor necrosis factor alpha medicine.symptom Cardiology and Cardiovascular Medicine Gremlin (protein) business |
| Zdroj: | Circulation Research. 119:434-449 |
| ISSN: | 1524-4571 0009-7330 |
| Popis: | Rationale: We have recently shown that the bone morphogenetic protein (BMP) antagonist Gremlin 2 (Grem2) is required for early cardiac development and cardiomyocyte differentiation. Our initial studies discovered that Grem2 is strongly induced in the adult heart after experimental myocardial infarction (MI). However, the function of Grem2 and BMP-signaling inhibitors after cardiac injury is currently unknown. Objective: To investigate the role of Grem2 during cardiac repair and assess its potential to improve ventricular function after injury. Methods and Results: Our data show that Grem2 is transiently induced after MI in peri-infarct area cardiomyocytes during the inflammatory phase of cardiac tissue repair. By engineering loss- ( Grem2 −/− ) and gain- ( TG Grem2 ) of-Grem2-function mice, we discovered that Grem2 controls the magnitude of the inflammatory response and limits infiltration of inflammatory cells in peri-infarct ventricular tissue, improving cardiac function. Excessive inflammation in Grem2 −/− mice after MI was because of overactivation of canonical BMP signaling, as proven by the rescue of the inflammatory phenotype through administration of the canonical BMP inhibitor, DMH1. Furthermore, intraperitoneal administration of Grem2 protein in wild-type mice was sufficient to reduce inflammation after MI. Cellular analyses showed that BMP2 acts with TNFα to induce expression of proinflammatory proteins in endothelial cells and promote adhesion of leukocytes, whereas Grem2 specifically inhibits the BMP2 effect. Conclusions: Our results indicate that Grem2 provides a molecular barrier that controls the magnitude and extent of inflammatory cell infiltration by suppressing canonical BMP signaling, thereby providing a novel mechanism for limiting the adverse effects of excessive inflammation after MI. |
| Databáze: | OpenAIRE |
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