title: Recombinant neuregulin 1 does not activate cardiomyocyte DNA synthesis in normal or infarcted adult mice.
abstract: OBJECTIVE
  Neuregulin 1 signaling plays an important role in cardiac trabecular development, and in sustaining functional integrity in adult hearts. Treatment with neuregulin 1 enhances adult cardiomyocyte differentiation, survival and/or function in vitro and in vivo. It has also been suggested that recombinant neuregulin 1β1 (NRG1β1) induces cardiomyocyte proliferation in normal and injured adult hearts. Here we further explore the impact of neuregulin 1 signaling on adult cardiomyocyte cell cycle activity.
  
  
  RESULTS
  Adult mice were subjected to 9 consecutive daily injections of recombinant NRG1β1 or vehicle, and cardiomyocyte DNA synthesis was quantitated via bromodeoxyuridine (BrdU) incorporation, which was delivered using mini-osmotic pumps over the entire duration of NRG1β1 treatment. NRG1β1 treatment inhibited baseline rates of cardiomyocyte DNA synthesis in normal mice (cardiomyocyte labelling index: 0.019±0.005% vs. 0.003±0.001%, saline vs. NRG1β1, P<0.05). Acute NRG1β1 treatment did result in activation of Erk1/2 and cardiac myosin regulatory light chain (down-stream mediators of neuregulin signalling), as well as activation of DNA synthesis in non-cardiomyocytes, validating the biological activity of the recombinant protein. In other studies, mice were subjected to permanent coronary artery occlusion, and cardiomyocyte DNA synthesis was monitored via tritiated thymidine incorporation which was delivered as a single injection 7 days post-infarction. Daily NRG1β1 treatment had no impact on cardiomyocyte DNA synthesis in the infarcted myocardium (cardiomyocyte labelling index: 0.039±0.011% vs. 0.027±0.021%, saline vs. NRG1β1, P>0.05).
  
  
  CONCLUSIONS
  These data indicate that NRG1β1 treatment does not increase cardiomyocyte DNA synthesis (and consequently does not increase the rate of cardiomyocyte renewal) in normal or infarcted adult mouse hearts. Thus, any improvement in cardiac structure and function observed following neuregulin treatment of injured hearts likely occurs independently of overt myocardial regeneration.
authors.affiliation: The Krannert Institute of Cardiology, and the Riley Heart Research Center, Wells Center for Pediatric Research, and Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Sean
authors.initials: S
authors.lastname: Reuter
authors.affiliation: The Krannert Institute of Cardiology, and the Riley Heart Research Center, Wells Center for Pediatric Research, and Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Soonpaa
authors.affiliation: The Krannert Institute of Cardiology, and the Riley Heart Research Center, Wells Center for Pediatric Research, and Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Firulli
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Audrey N
authors.initials: AN
authors.lastname: Chang
authors.affiliation: The Krannert Institute of Cardiology, and the Riley Heart Research Center, Wells Center for Pediatric Research, and Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Field
mesh_terms: D000818:Animals; D004247:DNA / Q000096:biosynthesis; D004261:DNA Replication / Q000187:drug effects*; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects; D020890:Neuregulin-1 / Q000494:pharmacology* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D020890:Neuregulin-1; D011994:Recombinant Proteins; D004247:DNA