Rapid onset of cardiomyopathy in STZ-induced female diabetic mice involves the downregulation of pro-survival Pim-1

Cardiovascular Diabetology

Original Investigation

Paolo Madeddu¹  Costanza Emanueli¹  Thrishila Parshu Ram²  Pujika E Munasinghe²  Andrew Moore²  Amol Shindikar²  Ingrid Fomison-Nurse²  Rajesh Katare²  Ivor F Galvin³  Richard W Bunton³  Pankaj Saxena⁴  Michael JA Williams⁵  Federica Riu⁵  Sean Coffey⁶ 

[1] Chair of Experimental Cardiovascular Medicine, School of Clinical Sciences, Bristol Heart Institute, University of Bristol, Bristol, UK;Department of Physiology-HeartOtago, Otago School of Medical Sciences, University of Otago, PO Box 913, 9054, Dunedin, New Zealand;Departments of Cardiothoracic Surgery, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand;Departments of Cardiothoracic Surgery, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand;The University of Western Australia, Perth, Australia;Departments of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand;Departments of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand;Oxford Biomedical Research Centre, Oxford, UK;

关键词: Diabetes;    Cardiomyopathy;    Gender difference;    Cardiac dysfunction;    Apoptosis;   

DOI  :  10.1186/1475-2840-13-68

 received in 2014-01-08, accepted in 2014-03-21,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundDiabetic 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.Methods and ResultsDiabetes 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.ConclusionsWe 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.

【 授权许可】

Unknown   
© Moore et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.