title: Mitogen-activated protein kinase kinase 1/2 inhibition and angiotensin II converting inhibition in mice with cardiomyopathy caused by lamin A/C gene mutation.
abstract: BACKGROUND
  Mutations in the LMNA gene encoding A-type nuclear lamins can cause dilated cardiomyopathy with or without skeletal muscular dystrophy. Previous studies have shown abnormally increased extracellular signal-regulated kinase 1/2 activity in hearts of Lmna(H222P/H222P) mice, a small animal model. Inhibition of this abnormal signaling activity with a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor has beneficial effects on heart function and survival in these mice. However, such treatment has not been examined relative to any standard of care intervention for dilated cardiomyopathy or heart failure. We therefore examined the effects of an angiotensin II converting enzyme (ACE) inhibitor on left ventricular function in Lmna(H222P/H222P) mice and assessed if adding a MEK1/2 inhibitor would provide added benefit.
  
  
  METHODS
  Male Lmna(H222P/H222P) mice were treated with the ACE inhibitor benazepril, the MEK1/2 inhibitor selumetinib or both. Transthoracic echocardiography was used to measure left ventricular diameters and fractional shortening was calculated.
  
  
  RESULTS
  Treatment of Lmna(H222P/H222P) mice with either benazepril or selumetinib started at 8weeks of age, before the onset of detectable left ventricular dysfunction, lead to statistically significantly increased fractional shortening compared to placebo at 16weeks of age. There was a trend towards a great value for fractional shortening in the selumetinib-treated mice. When treatment was started at 16weeks of age, after the onset of left ventricular dysfunction, the addition of selumetinib treatment to benazepril lead to a statistically significant increase in left ventricular fractional shortening at 20weeks of age.
  
  
  CONCLUSIONS
  Both ACE inhibition and MEK1/2 inhibition have beneficial effects on left ventricular function in Lmna(H222P/H222P) mice and both drugs together have a synergistic benefit when initiated after the onset of left ventricular dysfunction. These results provide further preclinical rationale for a clinical trial of a MEK1/2 inhibitor in addition to standard of care in patients with dilated cardiomyopathy caused by LMNA mutations.
authors.affiliation: Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY, USA; Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, NY, USA. Electronic address: a.muchir@institut-myologie.org.
authors.forename: Antoine
authors.initials: A
authors.lastname: Muchir
authors.affiliation: Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY, USA; Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, NY, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY, USA.
authors.forename: Fusako
authors.initials: F
authors.lastname: Sera
authors.affiliation: Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY, USA.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Homma
authors.affiliation: Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY, USA; Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, NY, USA. Electronic address: hjw14@columbia.edu.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Worman
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001552:Benzazepines; D001562:Benzimidazoles; D002311:Cardiomyopathy, Dilated / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D034904:Lamin Type A / Q000235:genetics*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D016896:Treatment Outcome
chemical_list: C517975:AZD 6244; D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D001562:Benzimidazoles; C494847:LMNA protein, human; D034904:Lamin Type A; D000804:Angiotensin II; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C044946:benazepril
keywords: Cardiomyopathy; Lamin; Mitogen-activated protein kinase; Nuclear envelope