Perturbations in myocardial energy metabolism in the ischemic heart

2020 ◽  
pp. 17-22
Keyword(s):  
Energy Metabolism ◽  
Oxidative Metabolism ◽  
Glucose Oxidation ◽  
Ischemic Heart ◽  
Acid Oxidation ◽  
Ischemia And Reperfusion ◽  
Metabolic Demand ◽  
Cardiac Efficiency ◽  
Myocardial Energy Metabolism ◽  
Oxidation Rates

As an organ that must continuously pump oxygenated blood throughout the body, the heart has an enormous metabolic demand, which is primarily met via oxidative metabolism of fatty acids and carbohydrates. Because of its high metabolic demand, during times of reduced oxygen supply such as ischemia, the heart becomes highly susceptible to injury, and if flow is not re-established, myocardial tissue is lost and can result in death (myocardial infarction). Of interest, both myocardial ischemia and reperfusion are associated with a number of perturbations in energy metabolism that contribute to the pathology of ischemic heart disease. This includes marked elevations in glycolysis to counteract the reduction in oxidative metabolism, whereas fatty acids predominate as the primary fuel source for residual oxidative metabolism. During the early stages of cardiac recovery after successful reperfusion of the ischemic heart, fatty acid oxidation rates also rapidly recover at the expense of low glucose oxidation rates. These metabolic perturbations increase myocardial acidosis due to glycolysis being uncoupled from glucose oxidation, which impairs cardiac efficiency. As such, therapeutic approaches to stimulate glucose oxidation or inhibit fatty acid oxidation have the potential to correct dysregulated myocardial energy metabolism during ischemia and reperfusion, which improves cardiac efficiency and may lead to improved clinical outcomes in people with ischemic heart disease. L

Barth Syndrome-Related Cardiomyopathy is Associated with a Reduction in Myocardial Glucose Oxidation

2021 ◽  
Author(s):  
Amanda A. Greenwell ◽  
Keshav Gopal ◽  
Tariq Altamimi ◽  
Christina T. Saed ◽  
Faqi Wang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Energy Metabolism ◽  
Glucose Oxidation ◽  
Genetic Disorder ◽  
Left Ventricular ◽  
Barth Syndrome ◽  
Acid Oxidation ◽  
Functional Impairments ◽  
Myocardial Energy Metabolism ◽  
Oxidation Rates

Heart failure presents as the leading cause of infant mortality in individuals with Barth syndrome (BTHS), a rare genetic disorder due to mutations in the tafazzin (TAZ) gene affecting mitochondrial structure and function. Investigations into the perturbed bioenergetics in the BTHS heart remain limited. Hence, our objective was to identify the potential alterations in myocardial energy metabolism and molecular underpinnings that may contribute to the early cardiomyopathy and heart failure development in BTHS. Cardiac function and myocardial energy metabolism were assessed via ultrasound echocardiography and isolated working heart perfusions, respectively, in a mouse model of BTHS (doxycycline-inducible Taz knockdown (TazKD) mice). In addition, we also performed mRNA/protein expression profiling for key regulators of energy metabolism in hearts from TazKD mice and their wild-type (WT) littermates. TazKD mice developed hypertrophic cardiomyopathy as evidenced by increased left ventricular anterior and posterior wall thickness, as well as increased cardiac myocyte cross sectional area, though no functional impairments were observed. Glucose oxidation rates were markedly reduced in isolated working hearts from TazKD mice compared to their WT littermates in the presence of insulin, which was associated with decreased pyruvate dehydrogenase activity. Conversely, myocardial fatty acid oxidation rates were elevated in TazKD mice, whereas no differences in glycolytic flux or ketone body oxidation rates were observed. Our findings demonstrate that myocardial glucose oxidation is impaired prior to the development of overt cardiac dysfunction in TazKD mice, and may thus represent a pharmacological target for mitigating the development of cardiomyopathy in BTHS.

scholarly journals Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

2016 ◽  
Vol 311 (2) ◽  
pp. H347-H363 ◽  
Author(s):  
Arata Fukushima ◽  
Osama Abo Alrob ◽  
Liyan Zhang ◽  
Cory S. Wagg ◽  
Tariq Altamimi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Energy Metabolism ◽  
Fatty Acid Oxidation ◽  
Glucose Oxidation ◽  
Acid Oxidation ◽  
Amino Acid Synthesis ◽  
Oxidation Rates ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy ◽  
The Impact

Dramatic maturational changes in cardiac energy metabolism occur in the newborn period, with a shift from glycolysis to fatty acid oxidation. Acetylation and succinylation of lysyl residues are novel posttranslational modifications involved in the control of cardiac energy metabolism. We investigated the impact of changes in protein acetylation/succinylation on the maturational changes in energy metabolism of 1-, 7-, and 21-day-old rabbit hearts. Cardiac fatty acid β-oxidation rates increased in 21-day vs. 1- and 7-day-old hearts, whereas glycolysis and glucose oxidation rates decreased in 21-day-old hearts. The fatty acid oxidation enzymes, long-chain acyl-CoA dehydrogenase (LCAD) and β-hydroxyacyl-CoA dehydrogenase (β-HAD), were hyperacetylated with maturation, positively correlated with their activities and fatty acid β-oxidation rates. This alteration was associated with increased expression of the mitochondrial acetyltransferase, general control of amino acid synthesis 5 like 1 (GCN5L1), since silencing GCN5L1 mRNA in H9c2 cells significantly reduced acetylation and activity of LCAD and β-HAD. An increase in mitochondrial ATP production rates with maturation was associated with the decreased acetylation of peroxisome proliferator-activated receptor-γ coactivator-1α, a transcriptional regulator for mitochondrial biogenesis. In addition, hypoxia-inducible factor-1α, hexokinase, and phosphoglycerate mutase expression declined postbirth, whereas acetylation of these glycolytic enzymes increased. Phosphorylation rather than acetylation of pyruvate dehydrogenase (PDH) increased in 21-day-old hearts, accounting for the low glucose oxidation postbirth. A maturational increase was also observed in succinylation of PDH and LCAD. Collectively, our data are the first suggesting that acetylation and succinylation of the key metabolic enzymes in newborn hearts play a crucial role in cardiac energy metabolism with maturation. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/acetylation-control-of-energy-metabolism-in-newborn-hearts/ .

Abstract 15649: Pharmacological Inhibition of Aldose Reductase by AT001 Prevents Abnormal Cardiac Energy Metabolism and Improves Heart Function in an Animal Model of Diabetic Cardiomyopathy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Keshav Gopal ◽  
Qutuba Karwi ◽  
Seyed Amirhossein Tabatabaei Dakhili ◽  
Riccardo Perfetti ◽  
Ravichandran Ramasamy ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Energy Metabolism ◽  
Fatty Acid Oxidation ◽  
Diabetic Cardiomyopathy ◽  
Acid Oxidation ◽  
Cardiac Energetics ◽  
Cardiac Efficiency ◽  
Oxidation Rates ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy

Introduction: Diabetic Cardiomyopathy (DCM) is a major cause of death in people with type 2 diabetes (T2D). Alterations in cardiac energy metabolism including increased fatty acid oxidation rates and reduced glucose oxidation rates are key contributing factors to the development of DCM. Studies have shown that Aldose Reductase (AR), an enzyme activated under hyperglycemic conditions, can modulate myocardial glucose and fatty acid oxidation, and promotes cardiac dysfunction. Hypothesis: Pharmacological inhibition of AR using a next-generation inhibitor AT-001, can mitigate DCM in mice by modulating cardiac energy metabolism and improving cardiac efficiency. Methods: Male human AR overexpressing (hAR-Tg) and C57BL/6J (Control) mice were subjected to experimental T2D (high-fat diet [60% kcal from lard] for 10-wk with a single intraperitoneal streptozotocin injection of 75 mg/kg) and treated for the last 3-wk with AT-001 (40mg/kg/day) or vehicle via oral gavage. Cardiac energy metabolism and in vivo cardiac function were assessed via isolated working heart perfusions and ultrasound echocardiography, respectively. Results: AT-001 treatment significantly improved cardiac energetics in a murine model of DCM (hAR-Tg mice with T2D). Particularly, AT-001-treated mice exhibited decreased cardiac fatty acid oxidation rates compared to the vehicle-treated mice (342 ± 53 vs 964 ± 130 nmol/min/g dry wt.). Concurrently, there was a significant decrease in cardiac oxygen consumption in the AT-001-treated compared to the vehicle-treated mice (41 ± 12 vs 60 ± 11 μmol/min/g dry wt.), suggesting increased cardiac efficiency. Furthermore, treatment with AT-001 prevented cardiac structural and functional abnormalities present in DCM, including diastolic dysfunction as reflected by an increase in the tissue Doppler E’/A’ ratio and decrease in E/E’ ratio. Moreover, AT-001 treatment prevented cardiac hypertrophy as reflected by a decrease in LV mass in AT-001-treated mice. Conclusions: AR inhibition with AT-001 prevents cardiac structural and functional abnormalities in a mouse model of DCM, and normalizes cardiac energetics by shifting cardiac metabolism towards a non-diabetic metabolic state.

scholarly journals The Contribution of Cardiac Fatty Acid Oxidation to Diabetic Cardiomyopathy Severity

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3259
Author(s):  
Qutuba G. Karwi ◽  
Qiuyu Sun ◽  
Gary D. Lopaschuk
Keyword(s):  
Cardiovascular Disease ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Energy Metabolism ◽  
Fatty Acid Oxidation ◽  
Diabetic Cardiomyopathy ◽  
Whole Body ◽  
Acid Oxidation ◽  
Cardiac Efficiency ◽  
Oxidation Rates

Diabetes is a major risk factor for the development of cardiovascular disease via contributing and/or triggering significant cellular signaling and metabolic and structural alterations at the level of the heart and the whole body. The main cause of mortality and morbidity in diabetic patients is cardiovascular disease including diabetic cardiomyopathy. Therefore, understanding how diabetes increases the incidence of diabetic cardiomyopathy and how it mediates the major perturbations in cell signaling and energy metabolism should help in the development of therapeutics to prevent these perturbations. One of the significant metabolic alterations in diabetes is a marked increase in cardiac fatty acid oxidation rates and the domination of fatty acids as the major energy source in the heart. This increased reliance of the heart on fatty acids in the diabetic has a negative impact on cardiac function and structure through a number of mechanisms. It also has a detrimental effect on cardiac efficiency and worsens the energy status in diabetes, mainly through inhibiting cardiac glucose oxidation. Furthermore, accelerated cardiac fatty acid oxidation rates in diabetes also make the heart more vulnerable to ischemic injury. In this review, we discuss how cardiac energy metabolism is altered in diabetic cardiomyopathy and the impact of cardiac insulin resistance on the contribution of glucose and fatty acid to overall cardiac ATP production and cardiac efficiency. Furthermore, how diabetes influences the susceptibility of the myocardium to ischemia/reperfusion injury and the role of the changes in glucose and fatty acid oxidation in mediating these effects are also discussed.

Abstract 282: Adropin Enhancement of Cardiac Insulin Sensitivity and Inhibition of Fatty Acid Oxidation are Associated With Improvement of Cardiac Function and Efficiency in Hearts From Fasted Mice

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Tariq R Altamimi ◽  
Arata Fukushima ◽  
Liyan Zhang ◽  
Su Gao ◽  
Abhishek Gupta ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Diabetic Cardiomyopathy ◽  
Insulin Signaling ◽  
Plasma Levels ◽  
Acid Oxidation ◽  
Post Translational Modification ◽  
Cardiac Efficiency ◽  
Oxidation Rates ◽  
Cardiac Energy

Impaired cardiac insulin signaling and high cardiac fatty acid oxidation rates are characteristics of diabetic cardiomyopathy. Potential roles for liver-derived metabolic factors in mediating cardiac energy homeostasis are underappreciated. Plasma levels of adropin, a liver secreted peptide, increase during feeding and decrease during fasting and diabetes. In skeletal muscle, adropin preferentially promotes glucose over fatty acid oxidation. We therefore determined what effect adropin has on cardiac energy metabolism, insulin signaling and cardiac efficiency. C57Bl/6 mice were fasted to accentuate the differences in adropin plasma levels between animals injected 3 times over 24 hr with either vehicle or adropin (450 nmol/kg i.p.). Despite fasting-induced predominance of fatty acid oxidation measured in isolated working hearts, insulin inhibition of fatty acid oxidation was re-established in adropin-treated mice (from 1022±143 to 517±56 nmol. g dry wt -1 . min -1 , p <0.05) compared to vehicle-treated mice (from 757±104 to 818±103 nmol. g dry wt -1 . min -1 ). Adropin-treated mice hearts showed higher cardiac work over the course of perfusion (p<0.05 vs. vehicle), which was accompanied by improved cardiac efficiency and enhanced phosphorylation of insulin signaling enzymes (tyrosine-IRS-1, AS160, p<0.05). Acute addition of adropin (2nM) to isolated working hearts from non-fasting mice showed a robust stimulation of glucose oxidation compared to vehicle-treated hearts (3025±401 vs 1708±292 nmol. g dry wt -1 . min -1 , p<0.05, respectively) with a corresponding inhibition of palmitate oxidation (325±61 vs 731±160 nmol. g dry wt -1 . min -1 , p<0.05, respectively), even in the presence of insulin. Acute adropin addition to hearts also increased IRS-1 tyrosine-phosphorylation as well as Akt, and GSK3β phosphorylation (p<0.05), suggesting acute receptor- and/or post-translational modification-mediated mechanisms. These results suggest adropin as a putative candidate for the treatment of diabetic cardiomyopathy.

Glucose and insulin improve cardiac efficiency and postischemic functional recovery in perfused hearts from type 2 diabetic (db/db) mice

2007 ◽  
Vol 292 (5) ◽  
pp. E1288-E1294 ◽  
Author(s):  
Anne D. Hafstad ◽  
Ahmed M. Khalid ◽  
Ole-Jakob How ◽  
Terje S. Larsen ◽  
Ellen Aasum
Keyword(s):  
Functional Recovery ◽  
Glucose Oxidation ◽  
Low Flow ◽  
Cardiac Complications ◽  
Acid Oxidation ◽  
Diabetic Patients ◽  
Cardiac Efficiency ◽  
Postischemic Recovery ◽  
Type 2 Diabetic

Hearts from type 2 diabetic ( db/ db) mice demonstrate altered substrate utilization with high rates of fatty acid oxidation, decreased functional recovery following ischemia, and reduced cardiac efficiency. Although db/ db mice show overall insulin resistance in vivo, we recently reported that insulin induces a marked shift toward glucose oxidation in isolated perfused db/ db hearts. We hypothesize that such a shift in metabolism should improve cardiac efficiency and consequently increase functional recovery following low-flow ischemia. Hearts from db/ db and nondiabetic ( db/+) mice were perfused with 0.7 mM palmitate plus either 5 mM glucose (G), 5 mM glucose and 300 μU/ml insulin (GI), or 33 mM glucose and 900 μU/ml insulin (HGHI). Substrate oxidation and postischemic recovery were only moderately affected by GI and HGHI in db/+ hearts. In contrast, GI and particularly HGHI markedly increased glucose oxidation and improved postischemic functional recovery in db/ db hearts. Cardiac efficiency was significantly improved in db/ db, but not in db/+ hearts, in the presence of HGHI. In conclusion, insulin and glucose normalize cardiac metabolism, restore efficiency, and improve postischemic recovery in type 2 diabetic mouse hearts. These findings may in part explain the beneficial effect of glucose-insulin-potassium therapy in diabetic patients with cardiac complications.

Adenosine modification of energy substrate use in isolated hearts perfused with fatty acids

1992 ◽  
Vol 262 (5) ◽  
pp. H1501-H1507 ◽  
Author(s):  
B. A. Finegan ◽  
A. S. Clanachan ◽  
C. S. Coulson ◽  
G. D. Lopaschuk
Keyword(s):  
Steady State ◽  
Glucose Oxidation ◽  
Acid Oxidation ◽  
Isolated Hearts ◽  
Oxidation Rates ◽  
Rat Hearts ◽  
Myocardial Substrate ◽  
14Co2 Production ◽  
Oxidation Ratio

The objective of this study was to determine the effect of adenosine on overall myocardial substrate utilization and mechanical function in isolated working rat hearts. Hearts were perfused with Krebs-Henseleit buffer containing 11 mM glucose (no fat) or with 11 mM glucose and 0.4 mM palmitate (normal fat). Steady-state rates of glycolysis, glucose oxidation, and fatty acid oxidation were measured by determination of quantitative 3H2O and 14CO2 production from radiolabeled substrates. The ratio of glycolysis (6.07 +/- 0.57 mumol.min-1.g dry wt-1) to glucose oxidation (3.12 +/- 0.28 mumol.min-1.g dry wt-1) under no fat conditions was 2:1. The addition of palmitate per se decreased glucose oxidation (to 0.81 +/- 0.09 mumol.min-1.g dry wt-1) and increased the glycolysis-to-glucose oxidation ratio to 6:1. Adenosine (100 microM) reduced this ratio to 3:1 by decreasing glycolysis (to 3.75 +/- 0.32 mumol.min-1.g dry wt-1) and increasing glucose oxidation (to 1.28 +/- 0.18 mumol.min-1.g dry wt-1) in the presence of palmitate. Steady-state palmitate oxidation rates were not altered by adenosine. Adenosine increased efficiency (work performed per unit O2 consumed) of spontaneously beating hearts but had no effect in paced hearts. These effects of adenosine on glucose metabolism may explain the beneficial actions of adenosine during reperfusion post ischemia.

A proteomic study of Shengmai injection's mechanism on preventing cardiac ischemia-reperfusion injury via energy metabolism modulation

2015 ◽  
Vol 11 (2) ◽  
pp. 540-548 ◽  
Author(s):  
Shuyu Zhan ◽  
Xiaohui Fan ◽  
Feng Zhang ◽  
Yi Wang ◽  
Liyuan Kang ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Reperfusion Injury ◽  
Metabolic Pathways ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Ischemia ◽  
Cardiac Efficiency ◽  
Myocardial Energy Metabolism ◽  
Shengmai Injection ◽  
Proteomic Study

Shengmai injection protects against IR injury through modulation of the myocardial energy metabolism to improve cardiac efficiency through multiple metabolic pathways.

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