title: Cardiomyocyte-specific transforming growth factor β suppression blocks neutrophil infiltration, augments multiple cytoprotective cascades, and reduces early mortality after myocardial infarction.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: From the Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD (P.P.R., S.H., D.I.L., N.K., D.A.K.); Division of Cardiology, Medical University of Graz, Austria (P.P.R.); Department of Pediatrics, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, OH (D.V., J.D.M.); Howard Hughes Medical Institute, University of Cincinnati, Cincinnati, OH (J.D.M.); and Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Gunma, Japan (N.K.).
authors.forename: Peter P
authors.initials: PP
authors.lastname: Rainer
authors.forename: Scarlett
authors.initials: S
authors.lastname: Hao
authors.forename: Davy
authors.initials: D
authors.lastname: Vanhoutte
authors.forename: Dong Ik
authors.initials: DI
authors.lastname: Lee
authors.forename: Norimichi
authors.initials: N
authors.lastname: Koitabashi
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D019610:Cytoprotection / Q000502:physiology*; D004195:Disease Models, Animal; D038702:Follistatin-Related Proteins / Q000378:metabolism; D055436:Growth Differentiation Factor 15 / Q000378:metabolism; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009504:Neutrophils / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D015996:Survival Rate; D019699:Thrombospondins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D038702:Follistatin-Related Proteins; C448720:Fstl1 protein, mouse; D055436:Growth Differentiation Factor 15; C506535:Il33 protein, mouse; C553108:Il33 protein, rat; D000067596:Interleukin-33; D007378:Interleukins; D019699:Thrombospondins; D016212:Transforming Growth Factor beta; C101864:thrombospondin 4; C448719:Fstl1 protein, rat
keywords: heart rupture; inflammation; myocardial infarction; neutrophils; transforming growth factor beta