title: Placental growth factor regulates cardiac inflammation through the tissue inhibitor of metalloproteinases-3/tumor necrosis factor-α-converting enzyme axis: crucial role for adaptive cardiac remodeling during cardiac pressure overload.
abstract: BACKGROUND
  Heart failure is one of the leading causes of mortality and is primarily the final stage of several overload cardiomyopathies, preceded by an early adaptive hypertrophic response and characterized by coordinated cardiomyocyte growth, angiogenesis, and inflammation. Therefore, growth factors and cytokines have to be critically regulated during cardiac response to transverse aortic constriction. Interestingly, the dual properties of placental growth factor as an angiogenic factor and cytokine make it a candidate to participate in cardiac remodeling in response to hemodynamic overload.
  
  
  RESULTS
  After transverse aortic constriction, placental growth factor knockout mice displayed a dysregulation of cardiac remodeling, negatively affecting muscle growth. Molecular insights underscored that this effect was ascribable mainly to a failure in the establishment of adequate inflammatory response owing to an impaired activity of tumor necrosis factor-α-converting enzyme. Interestingly, after transverse aortic constriction, placental growth factor knockout mice had strongly increased levels of tissue inhibitor of metalloproteinases-3, the main natural TACE inhibitor, thus indicating an unbalance of the tissue inhibitor of metalloproteinases-3/tumor necrosis factor-α-converting enzyme axis. Strikingly, when we used an in vivo RNA interference approach to reduce tissue inhibitor of metalloproteinases-3 levels in placental growth factor knockout mice during transverse aortic constriction, we obtained a complete phenotype rescue of early dilated cardiomyopathy.
  
  
  CONCLUSIONS
  Our results demonstrate that placental growth factor finely tunes a balanced regulation of the tissue inhibitor of metalloproteinases-3/tumor necrosis factor-α-converting enzyme axis and the consequent TNF-α activation in response to transverse aortic constriction, thus allowing the establishment of an inflammatory response necessary for adaptive cardiac remodeling.
authors: Department of Angiocardioneurology, IRCCS Neuromed, Pozzilli, Italy.
authors: Daniela
authors: D
authors: Carnevale
authors: Giuseppe
authors: G
authors: Cifelli
authors: Giada
authors: G
authors: Mascio
authors: Michele
authors: M
authors: Madonna
authors: Mauro
authors: M
authors: Sbroggiò
authors: Cinzia
authors: C
authors: Perrino
authors: Maria Grazia
authors: MG
authors: Persico
authors: Giacomo
authors: G
authors: Frati
authors: Giuseppe
authors: G
authors: Lembo
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism* / Q000502:physiology; D000072198:ADAM17 Protein; D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001011:Aorta / Q000503:physiopathology; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000503:physiopathology; D003331:Coronary Vessels / Q000503:physiopathology; D004195:Disease Models, Animal; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000188:drug therapy / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism* / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D017725:Ventricular Pressure / Q000187:drug effects / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*
chemical_list: C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D019717:Tissue Inhibitor of Metalloproteinase-3; D000072483:Placenta Growth Factor; D051722:ADAM Proteins; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse