Abstract
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.
Highlights
Diabetic women are five times more likely to develop congestive heart failure compared with two fold for men
These results suggest the requirement for the development of gender-specific treatments for diabetic cardiomyopathy
There was no significant difference between male and female diabetics at any corresponding time point, there was a clear trend for the female diabetics to have reduced E/A ratio throughout the study (Figure 1A)
Summary
Diabetic women are five times more likely to develop congestive heart failure compared with two fold for men. While non-diabetic women are relatively protected from cardiovascular disease, this advantage is series of 80 children and adolescents with well-controlled T1D, abnormalities in left ventricular dimensions and myocardial relaxation were reported, with the girls clearly being more affected than boys [13]. The reason for this global “female disadvantage” in diabetes remains largely unknown. Studies in animal models helped to elucidate potential pathogenic mechanisms of cardiomyopathy, but not to explain the interaction between gender and diabetes, as most available information derives from investigations performed in male rodents [14]. A deeper understanding of gender-related targets for stratified therapy is needed
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