title: Platelet endothelial cell adhesion molecule-1 mediates endothelial-cardiomyocyte communication and regulates cardiac function.
abstract: BACKGROUND
  Dilated cardiomyopathy is characterized by impaired contractility of cardiomyocytes, ventricular chamber dilatation, and systolic dysfunction. Although mutations in genes expressed in the cardiomyocyte are the best described causes of reduced contractility, the importance of endothelial-cardiomyocyte communication for proper cardiac function is increasingly appreciated. In the present study, we investigate the role of the endothelial adhesion molecule platelet endothelial cell adhesion molecule (PECAM-1) in the regulation of cardiac function.
  
  
  RESULTS
  Using cell culture and animal models, we show that PECAM-1 expressed in endothelial cells (ECs) regulates cardiomyocyte contractility and cardiac function via the neuregulin-ErbB signaling pathway. Conscious echocardiography revealed left ventricular (LV) chamber dilation and systolic dysfunction in PECAM-1(-/-) mice in the absence of histological abnormalities or defects in cardiac capillary density. Despite deficits in global cardiac function, cardiomyocytes isolated from PECAM-1(-/-) hearts displayed normal baseline and isoproterenol-stimulated contractility. Mechanistically, absence of PECAM-1 resulted in elevated NO/ROS signaling and NRG-1 release from ECs, which resulted in augmented phosphorylation of its receptor ErbB2. Treatment of cardiomyocytes with conditioned media from PECAM-1(-/-) ECs resulted in enhanced ErbB2 activation, which was normalized by pre-treatment with an NRG-1 blocking antibody. To determine whether normalization of increased NRG-1 levels could correct cardiac function, PECAM-1(-/-) mice were treated with the NRG-1 blocking antibody. Echocardiography showed that treatment significantly improved cardiac function of PECAM-1(-/-) mice, as revealed by increased ejection fraction and fractional shortening.
  
  
  CONCLUSIONS
  We identify a novel role for PECAM-1 in regulating cardiac function via a paracrine NRG1-ErbB pathway. These data highlight the importance of tightly regulated cellular communication for proper cardiac function.
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC (M.E.M.C., C.C., Z.C., E.T.).
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McCormick
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC (M.E.M.C., C.C., Z.C., E.T.).
authors.forename: Caitlin
authors.initials: C
authors.lastname: Collins
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (C.A.M., S.R.H.).
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Makarewich
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC (M.E.M.C., C.C., Z.C., E.T.).
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Chen
authors.affiliation: McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC (M.R., E.T.).
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rojas
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC (M.S.W.).
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (C.A.M., S.R.H.).
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC (M.E.M.C., C.C., Z.C., E.T.) McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC (M.R., E.T.).
authors.forename: Ellie
authors.initials: E
authors.lastname: Tzima
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology*; D002450:Cell Communication / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology; D006334:Heart Function Tests; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism*; D016133:Polymerase Chain Reaction / Q000379:methods; D012680:Sensitivity and Specificity; D013318:Stroke Volume / Q000502:physiology
chemical_list: D019408:Platelet Endothelial Cell Adhesion Molecule-1
keywords: PECAM‐1; cardiomyocyte; cardiomyopathy; endothelial cell; neuregulin‐1