Diabetic Cardiomyopathy in OVE26 Mice Shows Mitochondrial ROS Production and Divergence Between In Vivo and In Vitro Contractility

Abstract

■ AbstractMany diabetic patients suffer from a cardiomyopathy that cannot be explained solely by poor coronary perfusion. This cardiomyopathy may be due to either organ-based damage like fibrosis, or to direct damage to cardiomyocytes. Mitochondrial-derived reactive oxygen species (ROS) have been proposed to contribute to this cardiomyopathy. To address these questions, we used the OVE26 mouse model of severe type 1 diabetes to measure contractility in isolated cardiomyocytes by edge detection and in vivo with echocardiography. We also assessed the source of ROS generation using both a general and a mitochondrial specific indicator. When contractility was assayed in freshly isolated myocytes, contraction was much stronger in control myocytes. However, contractility of normal myocytes became weaker during 24 hours of in vitro culture. In contrast, contractility of diabetic OVE26 myocytes remains stable during culture. Echocardiography revealed normal or hyperdynamic function in OVE26 hearts under basal conditions but with a sharply reduced response to isoproterenol, a β-adrenergic agonist. For ROS generation, we found that ROS production in diabetic myocytes was elevated after exposure to either high glucose or angiotensin II (AngII). Superoxide detection with the mitochondrial sensor MitoSOX Red confirmed that mitochondria are a major source of ROS generation in diabetic myocytes. These results show that contractile deficits in OVE26 diabetic hearts are due primarily to cardiomyocyte impairment and that ROS from mitochondria are a cause of that impairment.

Lipid metabolism and its implications for type 1 diabetes-associated cardiomyopathy

“…Model name/parameter C57Bl/6J + STZ FVB/N + STZ OVE26 Akita Apoptosis ↑ Increased (Xu et al 2013) ↑ Increased (Wold et al 2006) ↑ Increased (Xie et al 2011, Xu et al 2013) Oxidative stress ↑ Increased (Kuramoto et al 2014, Westermann et al 2009, Xu et al 2013, Yan et al 2015 ↑ Increased (Wold et al 2006) ↑ Increased (Liang et al 2002, Ye et al 2004, Song et al 2007, Wang et al 2013, Xu et al 2013 Unchanged (Bugger et al 2008) Calcium mobilisation ↓ Decreased (Wold et al 2006) ↓ Decreased (Ye et al 2004, Kralik et al 2005 ↓ Decreased (Lu et al 2007, Bugger et al 2009, Mishra et al 2010, LaRocca et al 2012, Prathipati et al 2016 …”

Targeting caveolin-3 for the treatment of diabetic cardiomyopathy

“…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). The Akita mouse phenotype is characterised by only diastolic dysfunction (LaRocca, et al, 2012) whereas the OVE26 mouse exhibits impaired diastolic and systolic dysfunction.…”

Angiotensin II plays a critical role in diabetic pulmonary fibrosis most likely via activation of NADPH oxidase-mediated nitrosative damage

“…These mice were genetically engineered to carry a calmodulin minigene regulated by the rat insulin II promoter, with a fivefold increase in the content of calmodulin in ␤-cells (20,38,53). These OVE26 mice normally develop severe diabetes around 2 wk after birth, and they develop typical features of diabetic nephropathy and cardiomyopathy at 5 mo or older (20,38,53). Animals were euthanized at 3.5 mo after the onset of diabetes.…”