title: The effects of neuregulin on cardiac Myosin light chain kinase gene-ablated hearts.
abstract: BACKGROUND
  Activation of ErbB2/4 receptor tyrosine kinases in cardiomyocytes by neuregulin treatment is associated with improvement in cardiac function, supporting its use in human patients with heart failure despite the lack of a specific mechanism. Neuregulin infusion in rodents increases cardiac myosin light chain kinase (cMLCK) expression and cardiac myosin regulatory light chain (RLC) phosphorylation which may improve actin-myosin interactions for contraction. We generated a cMLCK knockout mouse to test the hypothesis that cMLCK is necessary for neuregulin-induced improvement in cardiac function by increasing RLC phosphorylation.
  
  
  RESULTS
  The cMLCK knockout mice have attenuated RLC phosphorylation and decreased cardiac performance measured as fractional shortening. Neuregulin infusion for seven days in wildtype mice increased cardiac cMLCK protein expression and RLC phosphorylation while increasing Akt phosphorylation and decreasing phospholamban phosphorylation. There was no change in fractional shortening. In contrast, neuregulin infusion in cMLCK knockout animals increased cardiac performance in the absence of cMLCK without increasing RLC phosphorylation. In addition, CaMKII signaling appeared to be enhanced in neuregulin-treated knockout mice.
  
  
  CONCLUSIONS
  Thus, Neuregulin may improve cardiac performance in the failing heart without increasing cMLCK and RLC phosphorylation by activating other signaling pathways.
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. audreyn.chang@utsouthwestern.edu
authors.forename: Audrey N
authors.initials: AN
authors.lastname: Chang
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.forename: Pavan K
authors.initials: PK
authors.lastname: Battiprolu
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
authors.forename: Kristine E
authors.initials: KE
authors.lastname: Kamm
authors.forename: James T
authors.initials: JT
authors.lastname: Stull
mesh_terms: D000818:Animals; D006321:Heart / Q000187:drug effects*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009219:Myosin-Light-Chain Kinase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D020880:Neuregulins / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020880:Neuregulins; D012333:RNA, Messenger; D009219:Myosin-Light-Chain Kinase