title: Cardiac CD47 drives left ventricular heart failure through Ca2+-CaMKII-regulated induction of HDAC3.
abstract: BACKGROUND
  Left ventricular heart failure (LVHF) remains progressive and fatal and is a formidable health problem because ever-larger numbers of people are diagnosed with this disease. Therapeutics, while relieving symptoms and extending life in some cases, cannot resolve this process and transplant remains the option of last resort for many. Our team has described a widely expressed cell surface receptor (CD47) that is activated by its high-affinity secreted ligand, thrombospondin 1 (TSP1), in acute injury and chronic disease; however, a role for activated CD47 in LVHF has not previously been proposed.
  
  
  RESULTS
  In experimental LVHF TSP1-CD47 signaling is increased concurrent with up-regulation of cardiac histone deacetylase 3 (HDAC3). Mice mutated to lack CD47 displayed protection from transverse aortic constriction (TAC)-driven LVHF with enhanced cardiac function, decreased cellular hypertrophy and fibrosis, decreased maladaptive autophagy, and decreased expression of HDAC3. In cell culture, treatment of cardiac myocyte CD47 with a TSP1-derived peptide, which binds and activates CD47, increased HDAC3 expression and myocyte hypertrophy in a Ca(2+)/calmodulin protein kinase II (CaMKII)-dependent manner. Conversely, antibody blocking of CD47 activation, or pharmacologic inhibition of CaMKII, suppressed HDAC3 expression, decreased myocyte hypertrophy, and mitigated established LVHF. Downstream gene suppression of HDAC3 mimicked the protective effects of CD47 blockade and decreased hypertrophy in myocytes and mitigated LVHF in animals.
  
  
  CONCLUSIONS
  These data identify a proximate role for the TSP1-CD47 axis in promoting LVHF by CaKMII-mediated up-regulation of HDAC3 and suggest novel therapeutic opportunities.
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (M.S.S., M.Q., J.B., S.F.S., H.C.C., J.S.I.) Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (M.S.S., H.C.C., J.S.I.).
authors.forename: Maryam
authors.initials: M
authors.lastname: Sharifi-Sanjani
authors.affiliation: Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA (A.H.S., H.C.C.).
authors.forename: Ali Hakim
authors.initials: AH
authors.lastname: Shoushtari
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (M.S.S., M.Q., J.B., S.F.S., H.C.C., J.S.I.).
authors.forename: Marisol
authors.initials: M
authors.lastname: Quiroz
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (M.S.S., M.Q., J.B., S.F.S., H.C.C., J.S.I.).
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Baust
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (M.S.S., M.Q., J.B., S.F.S., H.C.C., J.S.I.).
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Sestito
authors.affiliation: Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (M.M., M.R., C.M.S.C.).
authors.forename: Mackenzie
authors.initials: M
authors.lastname: Mosher
authors.affiliation: Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (M.M., M.R., C.M.S.C.).
authors.forename: Mark
authors.initials: M
authors.lastname: Ross
authors.affiliation: Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA (C.F.M.T.).
authors.forename: Charles F
authors.initials: CF
authors.lastname: McTiernan
authors.affiliation: Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (M.M., M.R., C.M.S.C.).
authors.forename: Claudette M
authors.initials: CM
authors.lastname: St Croix
authors.affiliation: Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA (R.A.B.).
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bilonick
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (M.S.S., M.Q., J.B., S.F.S., H.C.C., J.S.I.) Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (M.S.S., H.C.C., J.S.I.) Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA (A.H.S., H.C.C.).
authors.forename: Hunter C
authors.initials: HC
authors.lastname: Champion
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (M.S.S., M.Q., J.B., S.F.S., H.C.C., J.S.I.) Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (M.S.S., H.C.C., J.S.I.).
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Isenberg
mesh_terms: D000818:Animals; D051928:CD47 Antigen / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000502:physiology; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology*; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D032383:Myocytes, Cardiac / Q000502:physiology; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D000099186:Histone Deacetylase 3
chemical_list: D051928:CD47 Antigen; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D006655:Histone Deacetylases; D000099186:Histone Deacetylase 3; C497895:Cd47 protein, mouse
keywords: CD47; CaKMII; HDAC3; calcium; heart failure; thrombospondin‐1