Updating Experimental Models of Diabetic Cardiomyopathy

Fuentes-Antrás, Jesús; Picatoste, Belén; Gómez-Hernández, Almudena; Egido, Jesús; Tuñón, José; Lorenzo, Óscar

doi:10.1155/2015/656795

Cited by 63 publications

(60 citation statements)

References 155 publications

(177 reference statements)

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“…This included elevated fasting glucose (213 ± 13.5 mg/dL in HFD mice), insulin resistance (GTT and ITT), diastolic dysfunction (dp/dt min measured by catheterization), molecular evidence of fibrosis and hypertrophy (increased TGF-β and decreased SERCA-2A and β-MHC), and evidence of lipotoxicity. Other diet-induced DMCM models with HFD or high sucrose diets have produced mixed phenotypes [6]. HFD in rodent models seems to consistently deteriorate diastolic and systolic function measured after 6 to 16 weeks of treatment [30,31].…”

Section: Discussionmentioning

confidence: 99%

“…Metabolic syndrome from obesity leads to type 2 diabetes (T2DM) that progresses to diastolic dysfunction and diabetic cardiomyopathy (DMCM) [2][3][4]. In rodents, however, high-fat diet (HFD) models have produced inconclusive effects on cardiac dysfunction and remodeling, and thus the molecular mechanisms by which HFD leads to DMCM are not well established [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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Exercise Training Promotes Cardiac Hydrogen Sulfide Biosynthesis and Mitigates Pyroptosis to Prevent High-Fat Diet-Induced Diabetic Cardiomyopathy

et al. 2019

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Obesity increases the risk of developing diabetes and subsequently, diabetic cardiomyopathy (DMCM). Reduced cardioprotective antioxidant hydrogen sulfide (H 2 S) and increased inflammatory cell death via pyroptosis contribute to adverse cardiac remodeling and DMCM. Although exercise training (EX) has cardioprotective effects, it is unclear whether EX mitigates obesity-induced DMCM by increasing H 2 S biosynthesis and mitigating pyroptosis in the heart. C57BL6 mice were fed a high-fat diet (HFD) while undergoing treadmill EX for 20 weeks. HFD mice developed obesity, hyperglycemia, and insulin resistance, which were reduced by EX. Left ventricle pressure-volume measurement revealed that obese mice developed reduced diastolic function with preserved ejection fraction, which was improved by EX. Cardiac dysfunction was accompanied by increased cardiac pyroptosis signaling, structural remodeling, and metabolic remodeling, indicated by accumulation of lipid droplets in the heart. Notably, EX increased cardiac H 2 S concentration and expression of H 2 S biosynthesis enzymes. HFD-induced obesity led to features of type 2 diabetes (T2DM), and subsequently DMCM. EX during the HFD regimen prevented the development of DMCM, possibly by promoting H 2 S-mediated cardioprotection and alleviating pyroptosis. This is the first report of EX modulating H 2 S and pyroptotic signaling in the heart. mechanisms induced by EX to ameliorate cardiac dysfunction would lead to novel therapeutic targets for DMCM-especially in patients unable to exercise.Cardiomyocyte cell death is a key molecular event in the progression of DMCM, as the death of terminally differentiated cardiomyocytes leads to loss of contractile units and instigates fibrosis [12]. In metabolic syndrome, the diabetic environment of hyperglycemia, inflammatory cytokines, oxidative damage, and lipotoxicity induces several types of cell death, including non-inflammatory (apoptosis), and inflammatory (pyroptosis) cell death in the heart [13][14][15]. Pyroptosis is an inflammasome-mediated cell death mechanism where activation of the NOD-like receptor protein 3 (NLRP3) inflammasome activates caspase-1 and results in cell lysis and release of the interleukin IL-1β [16]. Hyperglycemia, fatty acids, and oxidative stress activate NLRP3 and caspase-1-mediated inflammasome, and inhibition of NLRP3 mitigates DMCM in diabetic rats [17][18][19]. Furthermore, HFD and obesity lead to inflammasome activation and infiltration of macrophages into adipose tissue, the key player in pyroptosis [18,20]. However, the role of pyroptosis in obesity-induced cardiac remodeling is unclear. Vandanmagsar et al. demonstrated that EX reduces pyroptotic cell death in adipose and liver tissue, however, this effect has not been evaluated in the heart [18].Hydrogen sulfide (H 2 S), a cardioprotective gaseous signaling molecule produced by homocysteine transsulfuration, prevents adverse cardiac remodeling and cell death, including pyroptosis [21]. H 2 S inhibits caspase-1 activity and IL-1β secretion both in vit...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exercise Training Promotes Cardiac Hydrogen Sulfide Biosynthesis and Mitigates Pyroptosis to Prevent High-Fat Diet-Induced Diabetic Cardiomyopathy

et al. 2019

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“…As one of the complications of high mortality caused by diabetes, DCM is receiving increasing attention. Cardiac hypertrophy is an important pathological process in DCM, which has a high correlation with the growing incidence of heart failure and sudden death in diabetic patients . For a comprehensive study in DMH it is essential to have a reliable and convenient animal model.…”

Section: Discussionmentioning

confidence: 99%

“…Cardiac hypertrophy is an important pathological process in DCM, which has a high correlation with the growing incidence of heart failure and sudden death in diabetic patients. 13 For a comprehensive study in DMH it is essential to have a reliable and convenient animal model. STZ, the most widely used chemical to induce diabetes, [14][15][16][17] selectively damages pancreatic cells, causes cell necrosis and results in reduced blood insulin and elevated blood sugar.…”

Section: Discussionmentioning

confidence: 99%

Establishment of a diabetic myocardial hypertrophy model in Mus musculus castaneus mouse

Zhang

Qiu

Huang

et al. 2018

Int J Experimental Path

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Summary The aim of this study was to establish a robust model of diabetic myocardial hypertrophy in Mus musculus castaneus mice. Mice were fed a high‐fat diet for four weeks and then given streptozotocin (STZ, 40 mg kg−1 d−1 for 5 days, intraperitoneally) and fasting blood glucose (FBG) levels were tested after seven days. Mice with FBG levels above 11.1 mmol/L were considered diabetic. Diabetic mice continued to have access to the high‐fat diet until cardiac hypertrophy developed. FBG and body weight (BW) were measured weekly. Myocardial hypertrophy was confirmed by left ventricle (LV) hypertrophy index (LVHI), LV/BW, LV histopathological observation and atrial natriuretic factor (ANF) mRNA expression. Serum insulin and plasma haemoglobin A1c (HbA1c) levels, total cholesterol (TCH) and triglyceride (TG) were measured, and then an insulin resistance index (HOMA.IR) was calculated. The level of FBG in the model group remained above 11.1 mmol/L, and the BW showed significant weight loss, compared with the control group (P < 0.01). The high levels of HbA1c, HOME.IR, TCH and TG, and the low level of insulin suggested that glucose metabolism was not balanced with insulin resistance; meanwhile, higher TCH and TG showed that dyslipidaemia had also developed. After the diabetic mice were kept on the high‐energy diet for another four weeks, histopathological observation showed myocardial injuries, much more surface area and collagen fibres, higher LVHI and LV/BW, and elevated expression of ANF mRNA (P < 0.01), suggesting that myocardial hypertrophy had appeared in Mus musculus castaneus mice under the current experimental conditions. Thus a robust model of diabetic myocardial hypertrophy was established four weeks after confirmation of diabetes, which was induced by feeding a high‐fat diet for four weeks combined with a repeated low‐dose STZ exposure, in Mus musculus castaneus mice.

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“…Data from animal models of diabetes do demonstrate relatively compelling structural, functional and metabolic cardiac changes that might be relevant in humans with diabetes 43. However, in this manuscript, we will focus on evidence for diabetic cardiomyopathy in humans.…”

Section: Pathophysiologymentioning

confidence: 99%