Cardiomyocyte-specific transforming growth factor β suppression blocks neutrophil infiltration, augments multiple cytoprotective cascades, and reduces early mortality after myocardial infarction

摘要

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 β (TGFβ). Broad inhibition of TGFβ 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 TGFβ signaling ameliorates postinfarct remodeling and inflammatory modulation and to identify mechanisms by which this may be achieved. Methods and results: Mice with TGFβ receptor-coupled signaling genetically suppressed only in cardiac myocytes (conditional TGFβ 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 TGFβ signaling led to 100% early mortality due to rupture. Rather than by altering fibrosis or reducing the generation of proinflammatory cytokines/chemokines, myocyte-selective TGFβ 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 TGFβ signaling as a potent regulator of protective cardiokine and neutrophil-mediated infarct remodeling.