title: Long-Term Biased β-Arrestin Signaling Improves Cardiac Structure and Function in Dilated Cardiomyopathy.
abstract: BACKGROUND
  Biased agonism of the angiotensin II receptor is known to promote cardiac contractility. Our laboratory indicated that these effects may be attributable to changes at the level of the myofilaments. However, these signaling mechanisms remain unknown. Because a common finding in dilated cardiomyopathy is a reduction in the myofilament-Ca2+response, we hypothesized that β-arrestin signaling would increase myofilament-Ca2+responsiveness in a model of familial dilated cardiomyopathy and improve cardiac function and morphology.
  
  
  METHODS
  We treated a dilated cardiomyopathy-linked mouse model expressing a mutant tropomyosin (Tm-E54K) for 3 months with either TRV120067, a β-arrestin 2-biased ligand of the angiotensin II receptor, or losartan, an angiotensin II receptor blocker. At the end of the treatment protocol, we assessed cardiac function using echocardiography, the myofilament-Ca2+response of detergent-extracted fiber bundles, and used proteomic approaches to understand changes in posttranslational modifications of proteins that may explain functional changes. We also assessed signaling pathways altered in vivo and by using isolated myocytes.
  
  
  RESULTS
  TRV120067- treated Tm-E54K mice showed improved cardiac structure and function, whereas losartan-treated mice had no improvement. Myofilaments of TRV120067-treated Tm-E54K mice had significantly improved myofilament-Ca2+responsiveness, which was depressed in untreated Tm-E54K mice. We attributed these changes to increased MLC2v and MYPT1/2 phosphorylation seen only in TRV120067-treated mice. We found that the functional changes were attributable to an activation of ERK1/2-RSK3 signaling, mediated through β-arrestin, which may have a novel role in increasing MLC2v phosphorylation through a previously unrecognized interaction of β-arrestin localized to the sarcomere.
  
  
  CONCLUSIONS
  Long-term β-arrestin 2-biased agonism of the angiotensin II receptor may be a viable approach to the treatment of dilated cardiomyopathy by not only preventing maladaptive signaling, but also improving cardiac function by altering the myofilament-Ca2+response via β-arrestin signaling pathways.
authors.affiliation: From Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago (D.M.R., J.L., B.R., B.M.W., R.J.S.); Department of Medicine, Division of Cardiology, University of Illinois at Chicago (B.M.W.); and Trevena, Inc. King of Prussia, PA (B.M.W.).
authors.forename: David M
authors.initials: DM
authors.lastname: Ryba
authors.affiliation: From Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago (D.M.R., J.L., B.R., B.M.W., R.J.S.); Department of Medicine, Division of Cardiology, University of Illinois at Chicago (B.M.W.); and Trevena, Inc. King of Prussia, PA (B.M.W.).
authors.forename: Jieli
authors.initials: J
authors.lastname: Li
authors.affiliation: From Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago (D.M.R., J.L., B.R., B.M.W., R.J.S.); Department of Medicine, Division of Cardiology, University of Illinois at Chicago (B.M.W.); and Trevena, Inc. King of Prussia, PA (B.M.W.).
authors.forename: Conrad L
authors.initials: CL
authors.lastname: Cowan
authors.affiliation: From Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago (D.M.R., J.L., B.R., B.M.W., R.J.S.); Department of Medicine, Division of Cardiology, University of Illinois at Chicago (B.M.W.); and Trevena, Inc. King of Prussia, PA (B.M.W.).
authors.forename: Brenda
authors.initials: B
authors.lastname: Russell
authors.affiliation: From Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago (D.M.R., J.L., B.R., B.M.W., R.J.S.); Department of Medicine, Division of Cardiology, University of Illinois at Chicago (B.M.W.); and Trevena, Inc. King of Prussia, PA (B.M.W.).
authors.forename: Beata M
authors.initials: BM
authors.lastname: Wolska
authors.affiliation: From Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago (D.M.R., J.L., B.R., B.M.W., R.J.S.); Department of Medicine, Division of Cardiology, University of Illinois at Chicago (B.M.W.); and Trevena, Inc. King of Prussia, PA (B.M.W.). solarorj@uic.edu.
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D006321:Heart / Q000000981:diagnostic imaging / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009210:Myofibrils / Q000187:drug effects / Q000378:metabolism; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014335:Tropomyosin / Q000235:genetics / Q000378:metabolism; D000071557:beta-Arrestins / Q000819:agonists* / Q000378:metabolism
chemical_list: D057911:Angiotensin Receptor Antagonists; C521958:Mylpf protein, mouse; D018994:Myosin Light Chains; D047428:Protein Kinase Inhibitors; D014335:Tropomyosin; D000071557:beta-Arrestins; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D043263:Myosin-Light-Chain Phosphatase; C510645:Ppp1r12a protein, mouse; D019808:Losartan; D002118:Calcium
keywords: TRV120027; TRV120067; biased ligand; calcium sensitivity; sarcomeres