Cardiomyocyte-Specific TGF β 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 (TGF  ). Broad inhibition of TGF  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 TGF  signaling suppresses post-infarct remodeling and inflammatory modulation, and identify mechanisms by which this may be achieved. Methods and Results : Mice with TGF β receptor-coupled signaling genetically suppressed only in cardiac myocytes (conditional TGF β 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 TGF β signaling led to 100% early mortality due to rupture. Rather than by altering fibrosis or reducing generation of proinflammatory cytokines/chemokines, myocyte-selective TGF β -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 TGF  signaling as a potent regulator of protective cardiokine and neutrophil mediated infarct remodeling. To in soft MA) for 10 days. Experiments were conducted 2-4 weeks after tamoxifen treatment when echocardiography confirmed normal baseline function. mice (Jackson Labs) were used in antibody studies. TGF β neutralizing antibody (clone 1D11) and control Ab (clone 13C4) were obtained from Genzyme, MA. Ab treatment was initiated at the time of LAD-ligation by intraperitoneal injection (10mg/kg BW, 3x/wk).