title: Rapid onset of cardiomyopathy in STZ-induced female diabetic mice involves the downregulation of pro-survival Pim-1.
abstract: BACKGROUND
  Diabetic women are five times more likely to develop congestive heart failure compared with two fold for men. The underlying mechanism for this gender difference is not known. Here we investigate the molecular mechanisms responsible for this female disadvantage and attempt safeguarding cardiomyocytes viability and function through restoration of pro-survival Pim-1.
  
  
  RESULTS
  Diabetes was induced by injection of streptozotocin in CD1 mice of both genders. Functional and dimensional parameters measurement using echocardiography revealed diastolic dysfunction in female diabetic mice within 8 weeks after STZ-induced diabetes. This was associated with significant downregulation of pro-survival Pim-1 and upregulation of pro-apoptotic Caspase-3, microRNA-1 and microRNA-208a. Male diabetic mice did not show any significant changes at this time point (P < 0.05 vs. female diabetic). Further, the onset of ventricular remodelling was quicker in female diabetic mice showing marked left ventricular dilation, reduced ejection fraction and poor contractility (P < 0.05 vs. male diabetic at 12 and 16 weeks of STZ-induced diabetes). Molecular analysis of samples from human diabetic hearts confirmed the results of pre-clinical studies, showing marked downregulation of Pim-1 in the female diabetic heart (P < 0.05 vs. male diabetic). Finally, in vitro restoration of Pim-1 reversed the female disadvantage in diabetic cardiomyocytes.
  
  
  CONCLUSIONS
  We provide novel insights into the molecular mechanisms behind the rapid onset of cardiomyopathy in female diabetics. These results suggest the requirement for the development of gender-specific treatments for diabetic cardiomyopathy.
authors.forename: Andrew
authors.initials: A
authors.lastname: Moore
authors.forename: Amol
authors.initials: A
authors.lastname: Shindikar
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fomison-Nurse
authors.forename: Federica
authors.initials: F
authors.lastname: Riu
authors.forename: Pujika E
authors.initials: PE
authors.lastname: Munasinghe
authors.forename: Thrishila Parshu
authors.initials: TP
authors.lastname: Ram
authors.forename: Pankaj
authors.initials: P
authors.lastname: Saxena
authors.forename: Sean
authors.initials: S
authors.lastname: Coffey
authors.forename: Richard W
authors.initials: RW
authors.lastname: Bunton
authors.forename: Ivor F
authors.initials: IF
authors.lastname: Galvin
authors.forename: Michael J A
authors.initials: MJ
authors.lastname: Williams
authors.forename: Costanza
authors.initials: C
authors.lastname: Emanueli
authors.forename: Paolo
authors.initials: P
authors.lastname: Madeddu
authors.affiliation: Department of Physiology-HeartOtago, Otago School of Medical Sciences, University of Otago, PO Box 913, Dunedin 9054, New Zealand. rajesh.katare@otago.ac.nz.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Katare
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism; D012727:Sex Characteristics; D013997:Time Factors
chemical_list: C496636:Pim1 protein, mouse; D051573:Proto-Oncogene Proteins c-pim-1