title: Cardiac thromboxane A2 receptor activation does not directly induce cardiomyocyte hypertrophy but does cause cell death that is prevented with gentamicin and 2-APB.
abstract: BACKGROUND
  We have previously shown that the thromboxane (TXA2) receptor agonist, U46619, can directly induce ventricular arrhythmias that were associated with increases in intracellular calcium in cardiomyocytes. Since TXA2 is an inflammatory mediator and induces direct calcium changes in cardiomyocytes, we hypothesized that TXA2 released during ischemia or inflammation could also cause cardiac remodeling.
  
  
  METHODS
  U46619 (0.1-10 μM) was applied to isolated adult mouse ventricular primary cardiomyocytes, mouse ventricular cardiac muscle strips, and cultured HL-1 cardiomyocytes and markers of hypertrophy and cell death were measured.
  
  
  RESULTS
  We found that TXA2 receptors were expressed in ventricular cardiomyocytes and were functional via calcium imaging. U46619 treatment for 24 h did not increase expression of pathological hypertrophy genes (atrial natriuretic peptide, β-myosin heavy chain, skeletal muscle α-actin) and it did not increase protein synthesis. There was also no increase in cardiomyocyte size after 48 h treatment with U46619 as measured by flow cytometry. However, U46619 (0.1-10 μM) caused a concentration-dependent increase in cardiomyocyte death (trypan blue, MTT assays, visual cell counts and TUNEL stain) after 24 h. Treatment of cells with the TXA2 receptor antagonist SQ29548 and inhibitors of the IP3 pathway, gentamicin and 2-APB, eliminated the increase in cell death induced by U46619.
  
  
  CONCLUSIONS
  Our data suggests that TXA2 does not induce cardiac hypertrophy, but does induce cell death that is mediated in part by IP3 signaling pathways. These findings may provide important therapeutic targets for inflammatory-induced cardiac apoptosis that can lead to heart failure.
authors.forename: Chad D
authors.initials: CD
authors.lastname: Touchberry
authors.forename: Neerupma
authors.initials: N
authors.lastname: Silswal
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tchikrizov
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Elmore
authors.forename: Shubra
authors.initials: S
authors.lastname: Srinivas
authors.forename: Adil S
authors.initials: AS
authors.lastname: Akthar
authors.forename: Hannah K
authors.initials: HK
authors.lastname: Swan
authors.forename: Lori A
authors.initials: LA
authors.lastname: Wetmore
authors.affiliation: Muscle Biology Group, School of Medicine, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA. wackerm@umkc.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wacker
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology; D006332:Cardiomegaly; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D005839:Gentamicins / Q000494:pharmacology; D008297:Male; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000235:genetics / Q000378:metabolism*
chemical_list: C538758:2-aminoethyl diphenylborinate; D001896:Boron Compounds; D005839:Gentamicins; D009124:Muscle Proteins; D012333:RNA, Messenger; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid