Pyridine Nucleotide Regulation of Cardiac Intermediary Metabolism

Ussher, John R.; Jaswal, Jagdip S.; Lopaschuk, Gary D.

doi:10.1161/circresaha.111.246371

Cited by 75 publications

(75 citation statements)

References 139 publications

(145 reference statements)

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“…G6P may also enter the pentose phosphate pathway (PPP) to produce NAD(P)H, which is essential for detoxifying cellular ROS (Ussher, et al, 2012). In addition, enzymes and products of the glycolytic pathway play an important role in cellular anabolism, as they may enter biosynthetic pathways such as the hexosamine biosynthetic pathway (HBP) to increase cellular biomass (Doenst, et al, 2013).…”

Section: Glucose Metabolismmentioning

confidence: 99%

Cardiac metabolism — A promising therapeutic target for heart failure

Noordali

Loudon

Frenneaux

et al. 2018

Pharmacology & Therapeutics

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Both heart failure with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF) are associated with high morbidity and mortality. Although many established pharmacological interventions exist for HFrEF, hospitalization and death rates remain high, and for those with HFpEF (approximately half of all heart failure patients), there are no effective therapies. Recently, the role of impaired cardiac energetic status in heart failure has gained increasing recognition with the identification of reduced capacity for both fatty acid and carbohydrate oxidation, impaired function of the electron transport chain, reduced capacity to transfer ATP to the cytosol, and inefficient utilization of the energy produced. These nodes in the genesis of cardiac energetic impairment provide potential therapeutic targets, and there is promising data from recent experimental and early-phase clinical studies evaluating modulators such as carnitine palmitoyltransferase 1 inhibitors, partial fatty acid oxidation inhibitors and mitochondrial-targeted antioxidants.Metabolic modulation may provide significant symptomatic and prognostic benefit for patients suffering from heart failure above and beyond guideline-directed therapy, but further clinical trials are needed.

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Section: Glucose Metabolismmentioning

confidence: 99%

Cardiac metabolism — A promising therapeutic target for heart failure

Noordali

Loudon

Frenneaux

et al. 2018

Pharmacology & Therapeutics

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“…Although metabolic remodeling in diabetes has been extensively studied (15,17,33,39), the involvement of redox metabolism in T2DM heart contractile dysfunction remains to be elucidated (53). To avoid misinterpretation, herein the term "redox" refers to the four main redox couples: NADH/NAD ϩ , NADPH/NADP ϩ , GSH/GSSG, and TrxSH 2 /TrxSS (21,36).…”

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confidence: 99%

Restoring redox balance enhances contractility in heart trabeculae from type 2 diabetic rats exposed to high glucose

Bhatt

Aon

Tocchetti

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Bhatt NM, Aon MA, Tocchetti CG, Shen X, Dey S, Ramirez-Correa G, O=Rourke B, Gao WD, Cortassa S. Restoring redox balance enhances contractility in heart trabeculae from type 2 diabetic rats exposed to high glucose. Am J Physiol Heart Circ Physiol 308: H291-H302, 2015. First published December 3, 2014; doi:10.1152/ajpheart.00378.2014.-Hearts from type 2 diabetic (T2DM) subjects are chronically subjected to hyperglycemia and hyperlipidemia, both thought to contribute to oxidizing conditions and contractile dysfunction. How redox alterations and contractility interrelate, ultimately diminishing T2DM heart function, remains poorly understood. Herein we tested whether the fatty acid palmitate (Palm), in addition to its energetic contribution, rescues function by improving redox [glutathione (GSH), NAD(P)H, less oxidative stress] in T2DM rat heart trabeculae subjected to high glucose. Using cardiac trabeculae from Zucker Diabetic Fatty (ZDF) rats, we assessed the impact of low glucose (EG) and high glucose (HG), in absence or presence of Palm or insulin, on force development, energetics, and redox responses. We found that in EG ZDF and lean trabeculae displayed similar contractile work, yield of contractile work (Ycw), representing the ratio of force time integral over rate of O2 consumption. Conversely, HG had a negative impact on Ycw, whereas Palm, but not insulin, completely prevented contractile loss. This effect was associated with higher GSH, less oxidative stress, and augmented matrix GSH/thioredoxin (Trx) in ZDF mitochondria. Restoration of myocardial redox with GSH ethyl ester also rescued ZDF contractile function in HG, independently from Palm. These results support the idea that maintained redox balance, via increased GSH and Trx antioxidant activities to resist oxidative stress, is an essential protective response of the diabetic heart to keep contractile function. contractile work; rate of respiration; redox environment; antioxidant systems; oxidative phosphorylation; mitochondrial ros emission; Zucker diabetic fatty rat A COMMON COMPLICATION OF TYPE 2 diabetes mellitus (T2DM) is cardiomyopathy, characterized by diastolic and systolic dysfunction, which is likely impacted by alterations in metabolic substrate availability. Although the healthy heart is flexible regarding fuel selection, the high levels of glucose and fat in T2DM lead to questions about which factors contribute to dysfunction and which are beneficial as energy source or redox donors (35).Fatty acids (FA) and glucose are the two major fuels driving heart contraction, and in T2DM and obesity existing evidence indicates increased FA oxidation (12, 15). The idea that FAs excess negatively regulates glucose oxidation in diabetes according to the Randle mechanism (33) remains a central postulate explaining some negative consequences of substrate shift in this metabolic disorder. However, it is now increasingly appreciated that hyperglycemia per se can trigger cellular damage, independently from FA utilization (11). The multiple mechanisms throug...

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“…Yet, there remains a significant number of patients who are refractory to conventional treatment, and thus, novel therapies to treat ischemic heart disease are necessary. One potential exciting new therapy involves the optimization of cardiac energy metabolism, which can be achieved via reducing myocardial fatty acid oxidation rates (Ussher and Lopaschuk, 2008;Jaswal et al, 2011;Ussher et al, 2012a).…”

Section: Introductionmentioning

confidence: 99%

Treatment with the 3-Ketoacyl-CoA Thiolase Inhibitor Trimetazidine Does Not Exacerbate Whole-Body Insulin Resistance in Obese Mice

Ussher

Keung

Fillmore

et al. 2014

J Pharmacol Exp Ther

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There is a growing need to understand the underlying mechanisms involved in the progression of cardiovascular disease during obesity and diabetes. Although inhibition of fatty acid oxidation has been proposed as a novel approach to treat ischemic heart disease and heart failure, reduced muscle fatty acid oxidation rates may contribute to the development of obesity-associated insulin resistance. Our aim was to determine whether treatment with the antianginal agent trimetazidine, which inhibits fatty acid oxidation in the heart secondary to inhibition of 3-ketoacyl-CoA thiolase (3-KAT), may have off-target effects on glycemic control in obesity. We fed C57BL/6NCrl mice a high-fat diet (HFD) for 10 weeks before a 22-day treatment with the 3-KAT inhibitor trimetazidine (15 mg/kg per day). Insulin resistance was assessed via glucose/insulin tolerance testing, and lipid metabolite content was assessed in gastrocnemius muscle. Trimetazidine-treatment led to a mild shift in substrate preference toward carbohydrates as an oxidative fuel source in obese mice, evidenced by an increase in the respiratory exchange ratio. This shift in metabolism was accompanied by an accumulation of long-chain acyl-CoA and a trend to an increase in triacylglycerol content in gastrocnemius muscle, but did not exacerbate HFD-induced insulin resistance compared with control-treated mice. It is noteworthy that trimetazidine treatment reduced palmitate oxidation rates in the isolated working mouse heart and neonatal cardiomyocytes but not C2C12 skeletal myotubes. Our findings demonstrate that trimetazidine therapy does not adversely affect HFD-induced insulin resistance, suggesting that treatment with trimetazidine would not worsen glycemic control in obese patients with angina.

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Pyridine Nucleotide Regulation of Cardiac Intermediary Metabolism

Cited by 75 publications

References 139 publications

Cardiac metabolism — A promising therapeutic target for heart failure

Cardiac metabolism — A promising therapeutic target for heart failure

Restoring redox balance enhances contractility in heart trabeculae from type 2 diabetic rats exposed to high glucose

Treatment with the 3-Ketoacyl-CoA Thiolase Inhibitor Trimetazidine Does Not Exacerbate Whole-Body Insulin Resistance in Obese Mice

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