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

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.

Targeting caveolin-3 for the treatment of diabetic cardiomyopathy

“…Some of the inconsistencies associated with for example protein expression levels may be associated with the size and frequency of the STZ dose, route of administration and the interval after injection that the animals are examined. Interestingly, a recent report has also shown that the development of cardiomyopathy, in the STZ female rat is more rapid than in the aged-matched male (Moore, et al, 2014); mirroring the human diabetic female predisposition to a higher mortality as described in the introduction. In addition to the STZ/alloxan models there are several genetically derived T1DM mouse models such as the Akita mouse (Ins2 Akita ) and the OVE26 mouse (Song, Du, Prabhu, & Epstein, 2007).…”

“…In addition, one of the studies employed both male and female animals e.g. (Malhotra, Penpargkul, Fein, Sonnenblick, & Scheuer, 1981), which may be a contributing factor leading to inconsistencies between reports, especially given the recent study showing that the onset and progression of DCM is more rapid in the female rats (Moore, et al, 2014).…”

Type-2 diabetes increases autophagy in the human heart through promotion of Beclin-1 mediated pathway

“…To determine if high glucose also increases the necrotic cell death, we measured the level of RIP kinase, whose activation has been demonstrated to promote necrotic cell death in the heart. [28,29] As shown in the supplemental Figure 3, there was no significant change in the expression pattern of RIP following high glucose treatment for 72h. This suggest that apoptosis is the major form of cell death in our experimental model.…”

Role of microRNA in diabetic cardiomyopathy: From mechanism to intervention

“…Ryanodine receptor Ca 2+ release channel complex (RyR2) located in sarcoplasmic reticulum is a target proteins for miR-1 in the diabetic heart, and exerts a vital role in Ca 2+ transport and cardiomyocyte contractility [84]. Moreover, miR-1 targets the 3′UTRs of MEF2A, transcription factor GATA binding protein 4 (GATA4), and other key cardiac-specific transcriptional factors such as heart and neural crest derivatives expressed 2 (Hand2), all of which exhibit essential role in myocardial differentiation, development and function [85–87]. MiR-208a, one of a positive regulator of hypertrophy is a cardiac-specific miRNA, and a possible inhibitor of Pim-1 expression [87].…”

“…Moreover, miR-1 targets the 3′UTRs of MEF2A, transcription factor GATA binding protein 4 (GATA4), and other key cardiac-specific transcriptional factors such as heart and neural crest derivatives expressed 2 (Hand2), all of which exhibit essential role in myocardial differentiation, development and function [85–87]. MiR-208a, one of a positive regulator of hypertrophy is a cardiac-specific miRNA, and a possible inhibitor of Pim-1 expression [87]. Overexpression of miR-208a leads to repression of myostatin and GATA4, as well as upregulation of β-myosin heavy chain (MHC) that contributes to cardiac hypertrophy [41, 54].…”