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Open Access Highly Accessed Original investigation

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

Andrew Moore1, Amol Shindikar1, Ingrid Fomison-Nurse1, Federica Riu3, Pujika E Munasinghe1, Thrishila Parshu Ram1, Pankaj Saxena25, Sean Coffey36, Richard W Bunton2, Ivor F Galvin2, Michael JA Williams3, Costanza Emanueli4, Paolo Madeddu4 and Rajesh Katare1*

Author Affiliations

1 Department of Physiology-HeartOtago, Otago School of Medical Sciences, University of Otago, PO Box 913, Dunedin 9054, New Zealand

2 Departments of Cardiothoracic Surgery, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

3 Departments of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

4 Chair of Experimental Cardiovascular Medicine, School of Clinical Sciences, Bristol Heart Institute, University of Bristol, Bristol, UK

5 The University of Western Australia, Perth, Australia

6 Oxford Biomedical Research Centre, Oxford, UK

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Cardiovascular Diabetology 2014, 13:68  doi:10.1186/1475-2840-13-68

Published: 1 April 2014

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.

Methods and 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.

Keywords:
Diabetes; Cardiomyopathy; Gender difference; Cardiac dysfunction; Apoptosis