期刊
CIRCULATION RESEARCH
卷 114, 期 8, 页码 1246-1257出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.114.302653
关键词
heart rupture; inflammation; myocardial infarction; neutrophils; transforming growth factor beta
资金
- National Institutes of Health (NHLBI) [HL-077180, HL-059480, HL-093432, HHSN268201000032C]
- Fondation Leducq TransAtlantic Network of Excellence
- Abraham and Virginia Weiss Professorship
- Peter Belfer Endowment
- Max Kade Fellowship of the Austrian Academy of Sciences
- American Heart Association Mid-Atlantic Fellowship
- National Institutes of Health [P01 NS072027]
Rationale: Wound healing after myocardial infarction involves a highly regulated inflammatory response that is initiated by the appearance of neutrophils to clear out dead cells and matrix debris. Neutrophil infiltration is controlled by multiple secreted factors, including the master regulator transforming growth factor (TGF). Broad inhibition of TGF early postinfarction has worsened post-myocardial infarction remodeling; however, this signaling displays potent cell specificity, and targeted suppression particularly in the myocyte could be beneficial. Objective: Our aims were to test the hypothesis that targeted suppression of myocyte TGF signaling ameliorates postinfarct remodeling and inflammatory modulation and to identify mechanisms by which this may be achieved. Methods and Results: Mice with TGF receptor-coupled signaling genetically suppressed only in cardiac myocytes (conditional TGF receptor 1 or 2 knockout) displayed marked declines in neutrophil recruitment and accompanying metalloproteinase 9 activation after infarction and were protected against early-onset mortality due to wall rupture. This is a cell-specific effect, because broader inhibition of TGF signaling led to 100% early mortality due to rupture. Rather than by altering fibrosis or reducing the generation of proinflammatory cytokines/chemokines, myocyte-selective TGF inhibition augmented the synthesis of a constellation of highly protective cardiokines. These included thrombospondin 4 with associated endoplasmic reticulum stress responses, interleukin-33, follistatin-like 1, and growth and differentiation factor 15, which is an inhibitor of neutrophil integrin activation and tissue migration. Conclusions: These data reveal a novel role of myocyte TGF signaling as a potent regulator of protective cardiokine and neutrophil-mediated infarct remodeling.
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