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

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Cardiovascular Diabetology

, 13:68

First Online: 01 April 2014Received: 08 January 2014Accepted: 21 March 2014


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.

KeywordsDiabetes Cardiomyopathy Gender difference Cardiac dysfunction Apoptosis AbbreviationsEDVEnd diastolic volume

ESVEnd systolic volume

HbA1cGlycosylated haemoglobin

HFHeart failure

LVAWLeft ventricular anterior wall

LVAWsLeft ventricular anterior wall in systole

LVAWdLeft ventricular anterior wall in diastole

LVEFLeft ventricular ejection fraction

LVESPLeft ventricular end systolic pressure

LVEDPLeft ventricular end diastolic pressure

MEMMinimal essential medium


Pim-1Proviral integration site for moloney murine leukemia virus-1


Electronic supplementary materialThe online version of this article doi:10.1186-1475-2840-13-68 contains supplementary material, which is available to authorized users.

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Autor: Andrew Moore - Amol Shindikar - Ingrid Fomison-Nurse - Federica Riu - Pujika E Munasinghe - Thrishila Parshu Ram - Pankaj 

Fuente: https://link.springer.com/article/10.1186/1475-2840-13-68

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