Type I Diabetic Akita Mouse Model is Characterized by Abnormal Cardiac Deformation During Early Stages of Diabetic Cardiomyopathy with Speckle-Tracking Based Strain Imaging

Zhou, Yingchao; Xiao, Hong; Wu, Jianfei; Zha, Lingfeng; Zhou, Ming; Li, Qianqian; Wang, Mengru; Shi, Shengwei; Li, Yanze; Lyu, Liangkun; Wang, Qing Kenneth; Tu, Xin; Lu, Qiulun

doi:10.1159/000487690

Cited by 16 publications

(11 citation statements)

References 24 publications

(27 reference statements)

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“…1b). At study end, body weight and tibial length were smaller in diabetic mice compared with wild type (Table 1), consistent with previous reports using this model [11]. Blood glucose and glycated haemoglobin levels were significantly elevated in Akita mice (Table 1).…”

Section: Characterisation Of Diabetes and Cardiac Dimensionssupporting

confidence: 89%

The Mitochondria-Targeted Methylglyoxal Sequestering Compound, MitoGamide, Is Cardioprotective in the Diabetic Heart

Tate

Higgins

Blasio

et al. 2019

Cardiovasc Drugs Ther

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Purpose Methylglyoxal, a by-product of glycolysis and a precursor in the formation of advanced glycation end-products, is significantly elevated in the diabetic myocardium. Therefore, we sought to investigate the mitochondria-targeted methylglyoxal scavenger, MitoGamide, in an experimental model of spontaneous diabetic cardiomyopathy. Methods Male 6-week-old Akita or wild type mice received daily oral gavage of MitoGamide or vehicle for 10 weeks. Several morphological and systemic parameters were assessed, as well as cardiac function by echocardiography. Results Akita mice were smaller in size than wild type counterparts in terms of body weight and tibial length. Akita mice exhibited elevated blood glucose and glycated haemoglobin. Total heart and individual ventricles were all smaller in Akita mice. None of the aforementioned parameters was impacted by MitoGamide treatment. Echocardiographic analysis confirmed that cardiac dimensions were smaller in Akita hearts. Diastolic dysfunction was evident in Akita mice, and notably, MitoGamide treatment preferentially improved several of these markers, including e′/a′ ratio and E/e′ ratio. Conclusions Our findings suggest that MitoGamide, a novel mitochondria-targeted approach, offers cardioprotection in experimental diabetes and therefore may offer therapeutic potential for the treatment of cardiomyopathy in patients with diabetes.

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Section: Characterisation Of Diabetes and Cardiac Dimensionssupporting

confidence: 89%

The Mitochondria-Targeted Methylglyoxal Sequestering Compound, MitoGamide, Is Cardioprotective in the Diabetic Heart

Tate

Higgins

Blasio

et al. 2019

Cardiovasc Drugs Ther

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“…Myocardial hypertrophy is not common in T1D patients and animal models of T1D [43]. Consistent with previous studies [44], we did not observe cardiac hypertrophy in the STZ-induced diabetic rats ( Table 2), proved that T1D and T2D may differentially impact the cardiac structure. Pathomorphological changes of myocardial tissue in DCM are associated with disruption of cell metabolism, increased collagen deposition and cardiomyocyte apoptosis [45,46].…”

Section: Discussionsupporting

confidence: 92%

Retinoid X receptor agonists attenuates cardiomyopathy in streptozotocin-induced type 1 diabetes through LKB1-dependent anti-fibrosis effects

Chai

Lin

Zheng³

et al. 2020

Clinical Science

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Diabetic cardiac fibrosis increases ventricular stiffness and facilitates the occurrence of diastolic dysfunction. Retinoid X receptor (RXR) plays an important role in cardiac development and has been implicated in cardiovascular diseases. In the present study, we investigated the effects of RXR agonist treatment on streptozotocin (STZ)-induced diabetic cardiomyopathy (DCM) and the underlying mechanism. Sprague–Dawley (SD) rats induced by STZ injection were treated with either RXR agonist bexarotene (Bex) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with high glucose (HG) with or without the indicated concentration of Bex or the RXR ligand 9-cis-retinoic acid (9-cis-RA). The protein abundance levels were measured along with collagen, body weight (BW), blood biochemical indexes and transforming growth factor-β (TGF-β) levels. The effects of RXRα down-regulation by RXRα small interfering RNA (siRNA) were examined. The results showed that bexarotene treatment resulted in amelioration of left ventricular dysfunction by inhibiting cardiomyocyte apoptosis and myocardial fibrosis. Immunoblot with heart tissue homogenates from diabetic rats revealed that bexarotene activated liver kinase B1 (LKB1) signaling and inhibited p70 ribosomal protein S6 kinase (p70S6K). The increased collagen levels in the heart tissues of DCM rats were reduced by bexarotene treatment. Treatment of CFs with HG resulted in significantly reduced LKB1 activity and increased p70S6K activity. RXRα mediated the antagonism of 9-cis-RA on HG-induced LKB1/p70S6K activation changes in vitro. Our findings suggest that RXR agonist ameliorates STZ-induced DCM by inhibiting myocardial fibrosis via modulation of the LKB1/p70S6K signaling pathway. RXR agonists may serve as novel therapeutic agents for the treatment of DCM.

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“…The diabetic milieu elicits changes in several cell types in the heart, including cardiomyocytes, cardiac fibroblasts, inflammatory cells and endothelial cells. These changes promote detrimental cardiac remodelling including cardiac hypertrophy, cardiomyocyte apoptosis and myocardial fibrosis (Bugyei-Twum et al, 2016; Russo and Frangogiannis, 2016; Tate et al, 2017b; Zhou et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Characterising an Alternative Murine Model of Diabetic Cardiomyopathy

et al. 2019

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The increasing burden of heart failure globally can be partly attributed to the increased prevalence of diabetes, and the subsequent development of a distinct form of heart failure known as diabetic cardiomyopathy. Despite this, effective treatment options have remained elusive, due partly to the lack of an experimental model that adequately mimics human disease. In the current study, we combined three consecutive daily injections of low-dose streptozotocin with high-fat diet, in order to recapitulate the long-term complications of diabetes, with a specific focus on the diabetic heart. At 26 weeks of diabetes, several metabolic changes were observed including elevated blood glucose, glycated haemoglobin, plasma insulin and plasma C-peptide. Further analysis of organs commonly affected by diabetes revealed diabetic nephropathy, underlined by renal functional and structural abnormalities, as well as progressive liver damage. In addition, this protocol led to robust left ventricular diastolic dysfunction at 26 weeks with preserved systolic function, a key characteristic of patients with type 2 diabetes-induced cardiomyopathy. These observations corresponded with cardiac structural changes, namely an increase in myocardial fibrosis, as well as activation of several cardiac signalling pathways previously implicated in disease progression. It is hoped that development of an appropriate model will help to understand some the pathophysiological mechanisms underlying the accelerated progression of diabetic complications, leading ultimately to more efficacious treatment options.

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Type I Diabetic Akita Mouse Model is Characterized by Abnormal Cardiac Deformation During Early Stages of Diabetic Cardiomyopathy with Speckle-Tracking Based Strain Imaging

Cited by 16 publications

References 24 publications

The Mitochondria-Targeted Methylglyoxal Sequestering Compound, MitoGamide, Is Cardioprotective in the Diabetic Heart

The Mitochondria-Targeted Methylglyoxal Sequestering Compound, MitoGamide, Is Cardioprotective in the Diabetic Heart

Retinoid X receptor agonists attenuates cardiomyopathy in streptozotocin-induced type 1 diabetes through LKB1-dependent anti-fibrosis effects

Characterising an Alternative Murine Model of Diabetic Cardiomyopathy

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