Cardiomyocyte-Specific TGFβ Suppression Blocks Neutrophil Infiltration, Augments Multiple Cytoprotective Cascades, and Reduces Early Mortality after Myocardial Infarction
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 beta (TGFβ). Broad inhibition of TGFβ early post-infarction has worsened post-MI remodeling; however, this signaling displays potent cell-specificity and targeted suppression particularly in the myocyte could be beneficial.
Objective: To test the hypothesis that targeted suppression of myocyte TGFβ signaling suppresses post-infarct remodeling and inflammatory modulation, and 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 was a cell-specific effect, as broader inhibition of TGFβ signaling led to 100% early mortality due to rupture. Rather than by altering fibrosis or reducing generation of pro-inflammatory cytokines/chemokines, myocyte-selective TGFβ-inhibition augmented 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 (GDF-15), which is an inhibitor of neutrophil integrin activation and tissue migration.
Conclusions: These data reveal a novel role of myocyte canonical TGFβ signaling as a potent regulator of protective cardiokine and neutrophil mediated infarct remodeling.
- Endoplasmic Reticulum Stress Response
- Myocardial infarction
- Infarct remodeling
- Irreversible injury
- Cardiac rupture
- Received September 18, 2013.
- Revision received February 21, 2014.
- Accepted February 26, 2014.