scholarly journals Characterisation of the Myocardial Mitochondria Structural and Functional Phenotype in a Murine Model of Diabetic Cardiomyopathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Alex M. Parker ◽  
Mitchel Tate ◽  
Darnel Prakoso ◽  
Minh Deo ◽  
Andrew M. Willis ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Low Dose ◽  
Body Weight Gain ◽  
Left Ventricular ◽  
Complex Iii ◽  
Diabetic Mice ◽  
High Fat ◽  
V Protein ◽  
Myocardial Mitochondria ◽  
Increased Risk

People affected by diabetes are at an increased risk of developing heart failure than their non-diabetic counterparts, attributed in part to a distinct cardiac pathology termed diabetic cardiomyopathy. Mitochondrial dysfunction and excess reactive oxygen species (ROS) have been implicated in a range of diabetic complications and are a common feature of the diabetic heart. In this study, we sought to characterise impairments in mitochondrial structure and function in a recently described experimental mouse model of diabetic cardiomyopathy. Diabetes was induced in 6-week-old male FVB/N mice by the combination of three consecutive-daily injections of low-dose streptozotocin (STZ, each 55 mg/kg i.p.) and high-fat diet (42% fat from lipids) for 26 weeks. At study end, diabetic mice exhibited elevated blood glucose levels and impaired glucose tolerance, together with increases in both body weight gain and fat mass, replicating several aspects of human type 2 diabetes. The myocardial phenotype of diabetic mice included increased myocardial fibrosis and left ventricular (LV) diastolic dysfunction. Elevated LV superoxide levels were also evident. Diabetic mice exhibited a spectrum of LV mitochondrial changes, including decreased mitochondria area, increased levels of mitochondrial complex-III and complex-V protein abundance, and reduced complex-II oxygen consumption. In conclusion, these data suggest that the low-dose STZ-high fat experimental model replicates some of the mitochondrial changes seen in diabetes, and as such, this model may be useful to study treatments that target the mitochondria in diabetes.

Exercise training prevents the development of cardiac dysfunction in the low-dose streptozotocin diabetic rats fed a high-fat diet

2013 ◽  
Vol 91 (1) ◽  
pp. 80-89 ◽  
Author(s):  
Riley A. Epp ◽  
Shanel E. Susser ◽  
Marc P. Morissette ◽  
D. Scott Kehler ◽  
Davinder S. Jassal ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Exercise Training ◽  
Protein Content ◽  
Cardiac Dysfunction ◽  
High Fat Diet ◽  
Low Dose ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
High Fat ◽  
Altered Expression

This study tested the hypothesis that exercise training would prevent the development of diabetes-induced cardiac dysfunction and altered expression of sarcoplasmic reticulum Ca2 +-transport proteins in the low-dose streptozotocin-induced diabetic rats fed a high-fat diet (HFD+STZ). Male Sprague–Dawley rats (4 weeks old; 125–150 g) were made diabetic using a high-fat diet (40% fat, w/w) and a low-dose of streptozotocin (35 mg·(kg body mass)–1) by intravenous injection. Diabetic animals were divided among a sedentary group (Sed+HFD+STZ) or an exercise-trained group (Ex+HFD+STZ) that accumulated 3554 ± 338 m·day–1 of voluntary wheel running (mean ± SE). Sedentary animals fed a low-fat diet served as the control (Sed+LFD). Oral glucose tolerance was impaired in the sedentary diabetic group (1179 ± 29; area under the curve (a.u.c.)) compared with that in the sedentary control animals (1447 ± 42 a.u.c.). Although left ventricular systolic function was unchanged by diabetes, impaired E/A ratios (i.e., diastolic function) and rates of pressure decay (–dP/dt) indicated the presence of diastolic dysfunction. Diabetes also reduced SERCA2a protein content and maximal SERCA2a activity (Vmax) by 21% and 32%, respectively. In contrast, the change in each parameter was attenuated by exercise training. Based on these data, it appears that exercise training prevented the development of diabetic cardiomyopathy and the dysregulation of sarcoplasmic reticulum protein content in an inducible animal model of type 2 diabetes.

Antidiabetic Effect of Sargassum wightii and Ulva fasciata in High Fat Diet and Multi Low Dose Streptozotocin Induced Type 2 Diabetic Mice

2016 ◽  
Vol 4 (2) ◽  
pp. 13 ◽  
Author(s):  
Lucy Mohapatra ◽  
Subrat Kumar Bhattamishra ◽  
Ramachandra Panigrahy ◽  
Sambit Parida ◽  
Premalata Pati
Keyword(s):  
High Fat Diet ◽  
Low Dose ◽  
Diabetic Mice ◽  
High Fat ◽  
Antidiabetic Effect ◽  
Ulva Fasciata ◽  
Sargassum Wightii ◽  
Type 2 Diabetic

scholarly journals Inulin oligofructose attenuates metabolic syndrome in high-carbohydrate, high-fat diet-fed rats

2016 ◽  
Vol 116 (9) ◽  
pp. 1502-1511 ◽  
Author(s):  
Senthil A. Kumar ◽  
Leigh C. Ward ◽  
Lindsay Brown
Keyword(s):  
Metabolic Syndrome ◽  
Corn Starch ◽  
Body Weight Gain ◽  
Fasting Blood Glucose ◽  
Plasma Concentrations ◽  
Left Ventricular ◽  
High Fat ◽  
Soluble Fibre ◽  
High Carbohydrate ◽  
The Metabolic Syndrome

AbstractPrebiotics alter bacterial content in the colon, and therefore could be useful for obesity management. We investigated the changes following addition of inulin oligofructose (IO) in the food of rats fed either a corn starch (C) diet or a high-carbohydrate, high-fat (H) diet as a model of diet-induced metabolic syndrome. IO did not affect food intake, but reduced body weight gain by 5·3 and 12·3 % in corn starch+inulin oligofructose (CIO) and high-carbohydrate, high-fat with inulin oligofructose (HIO) rats, respectively. IO reduced plasma concentrations of free fatty acids by 26·2 % and TAG by 75·8 % in HIO rats. IO increased faecal output by 93·2 %, faecal lipid excretion by 37·9 % and weight of caecum by 23·4 % and colon by 41·5 % in HIO rats. IO improved ileal morphology by reducing inflammation and improving the density of crypt cells in HIO rats. IO attenuated H diet-induced increases in abdominal fat pads (C 275 (sem 19), CIO 264 (sem 40), H 688 (sem 55), HIO 419 (sem 32) mg/mm tibial length), fasting blood glucose concentrations (C 4·5 (sem 0·1), CIO 4·2 (sem 0·1), H 5·2 (sem 0·1), HIO 4·3 (sem 0·1) mmol/l), systolic blood pressure (C 124 (sem 2), CIO 118 (sem 2), H 152 (sem 2), HIO 123 (sem 3) mmHg), left ventricular diastolic stiffness (C 22·9 (sem 0·6), CIO 22·9 (sem 0·5), H 27·8 (sem 0·5), HIO 22·6 (sem 1·2)) and plasma alanine transaminase (C 29·6 (sem 2·8), CIO 32·1 (sem 3·0), H 43·9 (sem 2·6), HIO 33·6 (sem 2·0) U/l). IO attenuated H-induced increases in inflammatory cell infiltration in the heart and liver, lipid droplets in the liver and plasma lipids as well as impaired glucose and insulin tolerance. These results suggest that increasing soluble fibre intake with IO improves signs of the metabolic syndrome by decreasing gastrointestinal carbohydrate and lipid uptake.

scholarly journals Conditional increase in SERCA2a protein is able to reverse contractile dysfunction and abnormal calcium flux in established diabetic cardiomyopathy

2008 ◽  
Vol 295 (5) ◽  
pp. R1439-R1445 ◽  
Author(s):  
Jorge Suarez ◽  
Brian Scott ◽  
Wolfgang H. Dillmann
Keyword(s):  
Cardiac Function ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Contractility ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Calcium Flux ◽  
Calcium Handling ◽  
Contractile Dysfunction ◽  
Diabetic Mice ◽  
Perfused Heart

Diabetic cardiomyopathy is characterized by reduced cardiac contractility independent of vascular disease. A contributor to contractile dysfunction in the diabetic heart is impaired sarcoplasmic reticulum function with reduced sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a) pump activity, leading to disturbed intracellular calcium handling. It is currently unclear whether increasing SERCA2a activity in hearts with existing diabetic cardiomyopathy could still improve calcium flux and contractile performance. To test this hypothesis, we generated a cardiac-specific tetracycline-inducible double transgenic mouse, which allows for doxycycline (DOX)-based inducible SERCA2a expression in which DOX exposure turns on SERCA2a expression. Isolated cardiomyocytes and Langendorff perfused hearts from streptozotocin-induced diabetic mice were studied. Our results show that total SERCA2a protein levels were decreased in the diabetic mice by 60% compared with control. SERCA2a increased above control values in the diabetic mice after DOX. Dysfunctional contractility in the diabetic cardiomyocyte was restored to normal by induction of SERCA2a expression. Calcium transients from diabetic cardiomyocytes showed a delayed rate of diastolic calcium decay of 66%, which was reverted toward normal after SERCA2a expression induced by DOX. Global cardiac function assessed in the diabetic perfused heart showed diminished left ventricular pressure, rate of contraction, and relaxation. These parameters were returned to control values by SERCA2a expression. In conclusion, we have used mice allowing for inducible expression of SERCA2a and could demonstrate that increased expression of SERCA2a leads to improved cardiac function in mice with an already established diabetic cardiomyopathy in absence of detrimental effects.

scholarly journals Sodium–glucose cotransporter 2 inhibitor Dapagliflozin attenuates diabetic cardiomyopathy

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
M. Arow ◽  
M. Waldman ◽  
D. Yadin ◽  
V. Nudelman ◽  
A. Shainberg ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Intracellular Calcium ◽  
Diabetic Cardiomyopathy ◽  
Ion Homeostasis ◽  
Left Ventricular ◽  
Calcium Transients ◽  
Diabetic Mice ◽  
Isolated Cardiomyocytes ◽  
Glucose Transporter 2

Abstract Background Diabetes mellitus type 2 (DM2) is a risk factor for developing heart failure but there is no specific therapy for diabetic heart disease. Sodium glucose transporter 2 inhibitors (SGLT2I) are recently developed diabetic drugs that primarily work on the kidney. Clinical data describing the cardiovascular benefits of SGLT2Is highlight the potential therapeutic benefit of these drugs in the prevention of cardiovascular events and heart failure. However, the underlying mechanism of protection remains unclear. We investigated the effect of Dapagliflozin—SGLT2I, on diabetic cardiomyopathy in a mouse model of DM2. Methods Cardiomyopathy was induced in diabetic mice (db/db) by subcutaneous infusion of angiotensin II (ATII) for 30 days using an osmotic pump. Dapagliflozin (1.5 mg/kg/day) was administered concomitantly in drinking water. Male homozygous, 12–14 weeks old WT or db/db mice (n = 4–8/group), were used for the experiments. Isolated cardiomyocytes were exposed to glucose (17.5–33 mM) and treated with Dapagliflozin in vitro. Intracellular calcium transients were measured using a fluorescent indicator indo-1. Results Angiotensin II infusion induced cardiomyopathy in db/db mice, manifested by cardiac hypertrophy, myocardial fibrosis and inflammation (TNFα, TLR4). Dapagliflozin decreased blood glucose (874 ± 111 to 556 ± 57 mg/dl, p < 0.05). In addition it attenuated fibrosis and inflammation and increased the left ventricular fractional shortening in ATII treated db/db mice. In isolated cardiomyocytes Dapagliflozin decreased intracellular calcium transients, inflammation and ROS production. Finally, voltage-dependent L-type calcium channel (CACNA1C), the sodium–calcium exchanger (NCX) and the sodium–hydrogen exchanger 1 (NHE) membrane transporters expression was reduced following Dapagliflozin treatment. Conclusion Dapagliflozin was cardioprotective in ATII-stressed diabetic mice. It reduced oxygen radicals, as well the activity of membrane channels related to calcium transport. The cardioprotective effect manifested by decreased fibrosis, reduced inflammation and improved systolic function. The clinical implication of our results suggest a novel pharmacologic approach for the treatment of diabetic cardiomyopathy through modulation of ion homeostasis.

Abstract 315: Coenzyme Q 10 Protects Against Diabetes-Induced Diastolic Dysfunction and Adverse Cardiac Remodeling in a Mouse Model of Type 1 Diabetes

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Karina Huynh ◽  
Helen Kiriazis ◽  
Xiao-Jun Du ◽  
Jane E Love ◽  
Karin Jandeleit-Dahm ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Diastolic Dysfunction ◽  
Olive Oil ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Remodeling ◽  
Coenzyme Q ◽  
Left Ventricular ◽  
Diabetic Patients ◽  
Diabetic Mice

Diastolic dysfunction is often the earliest manifestation of diabetic cardiomyopathy, usually accompanied by adverse cardiac remodeling and increased oxidative stress. We tested the hypothesis that administration of Coenzyme Q 10 (CoQ) attenuates type 1 diabetes-induced left ventricular (LV) dysfunction and remodeling. Further, we aimed to compare the efficacy of CoQ to the ACEI, ramipril. Male 6-week old mice received either streptozotocin (STZ, 55mg/kg/day for 5 days) to induce diabetes, or citrate buffer. After 4 weeks, mice were treated with either CoQ dissolved in olive oil (10mg/kg/day), olive oil alone, ramipril (3mg/kg/day) or left untreated for 8 weeks (n=11-14/group). Diabetic mice had increased blood glucose levels compared with non-diabetic controls. Superoxide (O 2 - ) production was enhanced in untreated diabetic mice, and attenuated with CoQ treatment. Diastolic function was impaired in diabetic mice, on Doppler echocardiography (E/A ratio, deceleration time DT) and catheterization (LV end diastolic pressure EDP and LV-dP/dt). Administration of CoQ ameliorated diastolic dysfunction on E/A ratio, DT and LVEDP in diabetic mice, with a similar trend on LV-dP/dt. Although DT and LVEDP were improved with ramipril treatment, E/A ratio was not. Diabetic mice also exhibited cardiomyocyte hypertrophy (H&E staining), cardiac fibrosis (Sirius red staining) and increased apoptosis. Both CoQ and ramipril reduced these markers of adverse LV remodeling. In conclusion, these data suggest that both CoQ and ramipril can attenuate diabetic cardiomyopathy. Addition of CoQ to standard care may offer improved treatment of diastolic dysfunction in diabetic patients.

FUNCTIONAL RESILIENCE OF C57BL/6J MOUSE HEART TO DIETARY FAT OVERLOAD

2021 ◽  
Author(s):  
Satya Murthy Tadinada ◽  
Eric T. Weatherford ◽  
Greg V. Collins ◽  
Gourav Bhardwaj ◽  
Jesse Cochran ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
High Fat Diet ◽  
Saturated Fat ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Mouse Heart ◽  
High Fat ◽  
Ventricular Ejection Fraction

Molecular mechanisms underlying cardiac dysfunction and subsequent heart failure in diabetic cardiomyopathy are incompletely understood. Initially we intended to test the role of GRK2, a potential mediator of cardiac dysfunction in diabetic cardiomyopathy, but found that control animals on HFD did not develop cardiomyopathy. Cardiac function was preserved in both wildtype and GRK2 knockout animals fed high fat diet as indicated by preserved left ventricular ejection fraction (LVEF) although heart mass was increased. The absence of cardiac dysfunction led us to rigorously evaluate the utility of diet-induced obesity to model diabetic cardiomyopathy in mice. Using pure C57BL/6J animals and various diets formulated with different sources of fat- lard (32% saturated fat, 68% unsaturated fat) or hydrogenated coconut oil (95% saturated fat), we consistently observed left ventricular hypertrophy, preserved LVEF and preserved contractility measured by invasive hemodynamics in animals fed high fat diet. Gene expression patterns that characterize pathological hypertrophy were not induced but a modest induction of various collagen isoforms and matrix metalloproteinases were observed in heart with high fat diet feeding. PPARa-target genes that enhance lipid utilization such as Pdk4, CD36, AcadL and Cpt1b were induced, but mitochondrial energetics were not impaired. These results suggest while long-term fat feeding in mice induces cardiac hypertrophy and increases cardiac fatty acid metabolism, it may not be sufficient to activate pathological hypertrophic mechanisms that impair cardiac function or induce cardiac fibrosis. Thus, additional factors that are currently not understood may contribute to the cardiac abnormalities previously reported by many groups.

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