Acid Metabolism In Heart Research Articles

Effects of High-Fat Feeding on Expression of Genes Regulating Fatty-1 Acid Metabolism in Hearts of Pregnant C57BL/6 Mice

Cardiovascular complications in pregnancy increase risk for subsequent heart disease, suggesting adverse events during pregnancy may permanently alter maternal heart health. The heart undergoes physiologic hypertrophy with pregnancy, which is distinct from pathological remodeling associated with obesity. We previously demonstrated that C57BL/6 mice fed a high-fat diet, a model of diet-induced obesity, had attenuated cardiac hypertrophy with pregnancy compared to low-fat controls, associated concentric remodeling. Dual effects of pregnancy and obesity on cardiac metabolism during hypertrophy have not been studied. We investigated whether expression of genes regulating fatty acid metabolism in the heart were altered in pregnant mice fed a high-fat diet. The Nanostring Metabolic Pathways Panel and nCounter analysis system was used to quantify individual mRNA transcripts of genes regulating fatty acid metabolism from the left ventricles of pregnant and non-pregnant female C57BL/6 mice fed a high-fat or control low-fat diet. Pregnancy increased expression of genes regulating fatty acid transport (Cd36, Slc27a1, Cpt1b) and β-oxidation (Acaa2, Acadl, Acox1, Ehhadh, Mlycd), but the effect was observed in low-fat mice only. Increases in gene expression with high-fat feeding were pronounced in non-pregnant mice, but effects not additive with pregnancy. Further, three genes with functions related to energy metabolism (Glul, Mat2a, Ogdhl,) were increased in low fat–fed pregnant mice only. Obesity during pregnancy may “max out” cardiac fatty acid utilization through upregulation of transporters and oxidation of long-chain fatty acids, and also downregulate metabolic pathways essential to cardiac adaptation. These 48 results suggest pre-existing obesity could disrupt cardiac physiologic remodeling during pregnancy.

In this Issue

HomeCirculation ResearchVol. 131, No. 3In this Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIn this Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published21 Jul 2022https://doi.org/10.1161/RES.0000000000000562Circulation Research. 2022;131:185Flavin Containing Monooxygenase 2 Prevents Cardiac Fibrosis via CYP2J3-SMURF2 Axis (p 189)FMO2 prevents heart fibrosis after injury, report Ni et al.Download figureDownload PowerPointEven if a patient survives a myocardial infarction (MI), the resulting fibrosis may impair heart function to such an extent the patient ultimately succumbs to heart failure. With the aim of informing fibrosis prevention and treatment strategies, Ni and colleagues searched for genes involved in the process. They performed a transcriptome analysis of heart tissue from rats that had or had not been subjected to MI and found that the gene for flavin-containing monooxygenase 2 (FMO2) was dramatically down-regulated in the MI hearts. Similarly, decreased FMO2 expression was observed in mouse, monkey and human heart tissue after MI. Suppression of FMO2 expression in the hearts of live rats prompted increased myocardial fibrosis and reduced heart function, while ramping up cardiac FMO2 expression immediately after MI reduced scarring and improved function in rodent and monkey hearts compared with controls. The team went on to determine the mechanism of FMO2’s anti-fibrotic effect, showing it interacted with the cytochrome CYP2J3 and disrupted SMAD signaling, which ultimately suppressed fibrotic genes. They also showed that such fibrotic genes could be suppressed in human cardiac scar fibroblasts by boosting FMO2–a strategy that could potentially be adapted clinically to reduce the risk of heart failure.SIRPα Mediates IGF1 Receptor in Cardiomyopathy-Induced by Chronic Kidney Disease (p 207)In chronic kidney disease, SIRPα impairs insulin signaling in the heart, say Thomas et al.Download figureDownload PowerPointCardiomyopathy is a common complication of chronic kidney disease (CKD), but what leads to the heart damage is not fully understood. CKD can exacerbate or induce high blood pressure, which in turn can damage the heart. However, signs of cardiomyopathy can occur at early stages of CKD when blood pressure might still be relatively normal. Thomas and colleagues suspected that signal regulatory protein α (SIRPα) might be an alternative trigger. Levels of SIRPα are elevated in the skeletal muscles of CKD model mice where the protein disrupts insulin signaling and causes muscle atrophy. Sure enough, the team’s new work shows SIRPα causes similar problems in the heart. SIRPα levels were elevated in the hearts of CKD mice and were correlated with impaired insulin/IGF1 receptor signaling, myocardial dysfunction and fibrosis. Furthermore, suppression of SIRPα in these CKD mice prevented myocardial fibrosis and improved heart function. Using biochemical analyses, the team revealed that SIRPα exerts its effect through direct interaction with, and inhibition of, the IGF1 receptor. Together the results suggest that SIRPα could be not only a marker of insulin resistance and cardiomyopathy in CKD, but also a clinical target for treating or preventing this heart damage.Mitochondrial H2S Regulates BCAA Catabolism in Heart Failure (p 222)Li et al suggest a link between hydrogen sulfide production and animo acid metabolism in heart failure.Download figureDownload PowerPointWhile hydrogen sulfide (H2S) is poisonous to humans if inhaled, evidence suggests in its endogenously produced form it protects the heart from myocardial infarction, arrhythmia and other heart-damaging conditions. One of the cellular H2S-producing enzymes is 3-mercaptopyruvate sulfurtransferase (3-MST) and, after a heart injury, mice lacking this enzyme have exacerbated cardiac dysfunction and severe exercise intolerance compared with control animals. To understand how 3-MST might protect the heart, Li and colleagues performed a metabolomic screen in mice with and without 3-MST and found those lacking the enzyme had defects in their catabolism of the branched-chain amino acids (BCAAs) leucine, isoleucine and valine. Importantly, pharmacologically reducing the levels of these BCAAs attenuated the effects of injury in the hearts of 3-MST-lacking mice and control animals. It is not clear how 3-MST regulates BCAA catabolism, but the team’s finding that heart tissue from patients with end-stage heart failure has unusually low levels of 3-MST, suggests it would be worthwhile examining BCAA catabolism in such tissue too. If the results hold true, then modulation of 3-MST, or indeed BCAAs or H2S, could be investigated as potential treatment strategies. 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P3478Glucose-dependent insulinotropic peptide is essential for maintenance of cardiac lipid metabolism via FGF21-dependent pathway

Abstract Background/Introduction Incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are secreted from the small intestine and emerged as important participants in glucose homeostasis that involves in the pathogenesis of type 2 diabetes (T2D). stimulate glucose-dependent insulin biosynthesis. Emerging data suggest important extrapancreatic functions for GLP-1 on cardiovascular system. However, limited evidence has been emerged whether GIP may play any pathophysiological role in heart. GIP promotes insulin secretion leading to augment insulin-induced lipogenesis. Recent research has highlighted the relevance of the GIP/GIPR axis in principal insulin-sensitive organs such as adipose tissue. Heart is another insulin-sensitive organ in which insulin promotes hypertrophy of myocardium presumably via activation of Akt pathway. In T2DM, ectopic accumulation of lipid and fat to myocardium that is known as “cardiac steatosis”; however, it remains uncertain whether the GIP/insulin axis may modulate cardiac steatosis observed in T2DM. Purpose To elucidate that physiological GIP may play a regulatory role in cardiac pathophysiology. Methods We employed mouse model of GIPR deficiency (GIPR-KO) that was generated by lacking the GIPR gene (GIPR), by replacing exons 4 and 5 of GIPR with the PGK-neo cassette. Cardiac evaluation of GIPR-KO was performed at the age of 6 week-old (w/o), 10 w/o, 23 w/o, and 53 w/o. Results GIPR deficient mice (GIPR-KO) exhibited normoglycemia, but their circulating free acid level and ketone level were elevated. Interestingly, GIPR-KO at younger age (6-week-old and 10-week old) exhibited normal left-ventricular (LV) function, however, older mice aged older than 20-week-old exhibited significant systolic left-ventricular dysfunction (FS (%) 55.2±1.9 for Wild-type, 32.1±2.6 for 23-w/o-GIPR-KO, 28.5±2.6 for 56-w/o-GIPR-KO, P<0.01). Histological analysis revealed that cardiomyocyte size was decreased and capillary density was increased in GIPR-KO. Interestingly, TUNEL staining revealed that there was no increase in cardiac apoptosis in GIPR-KO. In contrast, GIPR-KO exhibited increase in cardiac fibrosis (Picro-sirius staining) and oxidative stress (DHE staining). Myocardial triglyceride accumulation was decreased in GIPR-KO heart. QPCR analysis revealed GIPR-KO heart exhibited increase in BNP level and decline in fibroblast growth factor 21 (FGF-21), an hormonal activator for energy expenditure in adipocyte. GIP augmented FGF-21 expression in cardiomyocytes via PPARalfa. Conclusion Loss of GIP signaling caused impaired fatty acid metabolism in heart via impairment of FGF21 pathway and oxidative stress, leading to an age-dependent progression of cardiac dysfunction.

Heart Metabolic Responses to Exertional Heat Stroke Are Dependent Upon Sex

In virtually all eukaryotic organisms, sex is an important variable affecting many physiological functions. In exertional heat stroke (EHS), the cardiac muscle plays a dual role to pump blood to the active skeletal muscles and to the periphery for heat exchange, but whether the metabolic responses occurring in the cardiac muscle after EHS are sex‐dependent remains unknown. In our pre‐clinical model of EHS, female mice run longer in the heat and this advantage seems to be regardless of body size. Our aim was to determine sex differences in cardiac muscle's metabolic biomarkers in response to a single session of EHS. Sixteen male and 16 female C57BL6J mice were trained to run on an incremental forced running wheel and were exposed to 37.5°C/~40% relative humidity while running to induce EHS. Hearts were harvested 3 h after the EHS trial. Control mice ran for the same relative duration and were sacrificed 4 days after the trial. Metabolites were extracted from the heart and analyzed by mass spectrometry. Metabolites were matched to a library of standards for identification and quantification. Time to achieve EHS was 121.16 ± 22 min for males and 189.25 ± 35 for females (p<0.05). Glucose‐6‐phosphate (G‐6‐P) increased 2‐fold in males after EHS in comparison to control and remained unchanged in females. Males had a 2‐fold higher G‐6‐P concentration after EHS in comparison to females (p<0.05). These changes highlight a greater reliance on glycolytic pathways in the heart for males after EHS. While pyruvate was unchanged in males compared to control, we observed an increase after EHS in females compared to their matched controls (p<0.05). After EHS, females exhibited a higher pyruvate content in comparison to males (p<0.05). The accumulation of pyruvate in females suggests a greater reliance on fatty acid metabolism in the heart after EHS. All branched chain amino acids (leucine, isoleucine and valine) increased in both sexes after EHS (p<0.05), but we did not observe differences between sexes. While the content of palmitoylcarnitine decreased 0.5‐fold after EHS in males, we observed the reverse in females, a 0.5‐fold increase (p<0.05). Likewise, stearoylcarnitine increased in females after EHS, but remained unchanged in males (p<0.05). Because both carnitine metabolites may serve as a substrate for carnitine palmitoyl transferase enzymatic system, which is critical for fatty acid metabolism, we interpret this as evidence of greater reliance on fatty acid metabolism in female heart in comparison to males. In conclusion, we observed relevant and distinct metabolic changes in males versus females after EHS, consistent with female heart having a greater capacity to rely on fatty acid metabolism in comparison to males. Whether these differences explain the more resistant phenotype observed in females during EHS remains to be determined. The opinions or assertions contained herein are the private views of the author(s) and are not to be construed as official or reflecting the views of the Army or the DoD.Support or Funding InformationDOD Grant W81XWH‐15‐2‐0038This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Abstract P119: Erythrocyte n-3 and n-6 Polyunsaturated and Trans Fatty Acids and Survival of Sudden Cardiac Arrest

Lower levels of erythrocyte n-3 polyunsaturated fatty acid (PUFA) and higher levels of trans-fatty acid are associated with incident cardiac arrest (SCA) risk. However, it is not known whether these fatty acids also influence post-arrest survival. In addition, n-3 and n-6 PUFA play key roles in brain function and may be involved in brain resuscitation. We investigated the association of n-3, n-6 and trans-fatty acid levels with resuscitation outcomes in a population-based study of SCA. Subjects (mean age 68, 82% male) were out-of-hospital SCA patients found in ventricular fibrillation and attended by paramedics in King County, Washington, with available fatty acid measurements (n=492). Using logistic regression, we examined association between fatty acid levels and surviving to hospital admission (a proxy for heart resuscitation), and also to surviving to hospital discharge (a proxy for brain resuscitation). Both analyses adjusted for age; sex; race; year of cardiac arrest; time to arrival of emergency medical services; whether the event was witnessed, occurred in public, and whether bystander CPR was administered. Levels of arachidonic acid and trans-18:2 fatty acids were associated with SCA survival ( Table ). An increase of one SD in levels of arachidonic acid was associated with decreased likelihood of survival to both hospital admission and hospital discharge (OR (95% CI), uncorrected p-value: 0.75 (0.62-0.92), p =0.006 and 0.69 (0.55, 0.87), p =0.002, respectively). A one SD difference in trans-18:2 fatty acid levels was associated with decreased likelihood of survival to hospital discharge (0.74 (0.57-0.96), p =0.02)). Levels of n-3 PUFAs and trans-18:1 fatty acids were not associated with SCA survival. Our findings suggest arachidonic acid and trans-18:2 may influence SCA survival. Further work is needed to explore the role of fatty acid metabolism in heart and brain resuscitation. Association of Erythrocyte Fatty Acids with Resuscitation Outcomes Survival to hospital admission Survival to hospital discharge OR * (95% CI) p-value OR * (95% CI) p-value n-3 fatty acids α-Linolenic acid 1.01 (0.83-1.22) 0.95 0.85 (0.67-1.07) 0.60 EPA+DHA 1.05 (0.87-1.28) 0.60 1.10 (0.87-1.38) 0.44 n-6 fatty acids Linoleic acid 0.97 (0.80-1.18) 0.77 1.05 (0.83-1.33) 0.66 Arachidonic acid 0.75 (0.62-0.92) 0.006 0.69 (0.55-0.87) 0.002 Trans-fatty acids Trans-18:1 1.06 (0.87-1.29) 0.56 1.06 (0.84-1.34) 0.47 Trans-18:2 0.99 (0.80-1.22) 0.93 0.74 (0.57-0.96) 0.02 * OR corresponding to one SD higher levels

Is PPARα intron 7 G/C polymorphism associated with muscle strength characteristics in nonathletic young men?

Peroxisome proliferator-activated receptor alpha (PPARα), a ligand-dependent transcription factor, regulates fatty acid metabolism in heart and skeletal muscle. The intron 7 G/C polymorphism (rs4253778) has been associated with athletic performance. The rare C-allele was predominant in power athletes, whereas the G-allele was more frequent in endurance athletes. In the present study, we investigated the association between this polymorphism and strength characteristics in nonathletic, healthy young adults (n = 500; age 24.2 ± 4.4 years). Knee torque was measured during concentric knee flexion and extension movements at 60°/s, 120°/s, and 240°/s during 3, 25, and 5 repetitions, respectively. Also, resistance to muscle fatigue (i.e. work last 20% repetitions/work first 20% repetitions *100) was calculated. Differences in knee strength phenotypes between GG homozygous individuals and C-allele carriers were analyzed. The polymorphism did not influence the ability to produce isometric or dynamic knee flexor or extensor peak torque during static or dynamic conditions in this population (0.23 < P < 0.95). Similar results were found for the endurance ratio, a measure for resistance to muscle fatigue. In conclusion, the PPARα intron 7 G/C polymorphism does not seem to influence strength characteristics in a nonathletic population.

Longitudinal Evaluation of Fatty Acid Metabolism in Normal and Spontaneously Hypertensive Rat Hearts with Dynamic MicroSPECT Imaging

The goal of this project is to develop radionuclide molecular imaging technologies using a clinical pinhole SPECT/CT scanner to quantify changes in cardiac metabolism using the spontaneously hypertensive rat (SHR) as a model of hypertensive-related pathophysiology. This paper quantitatively compares fatty acid metabolism in hearts of SHR and Wistar-Kyoto normal rats as a function of age and thereby tracks physiological changes associated with the onset and progression of heart failure in the SHR model. The fatty acid analog, 123I-labeled BMIPP, was used in longitudinal metabolic pinhole SPECT imaging studies performed every seven months for 21 months. The uniqueness of this project is the development of techniques for estimating the blood input function from projection data acquired by a slowly rotating camera that is imaging fast circulation and the quantification of the kinetics of 123I-BMIPP by fitting compartmental models to the blood and tissue time-activity curves.

Evidence for concerted action of FAT/CD36 and FABPpm to increase fatty acid transport across the plasma membrane

There is substantial molecular, biochemical and physiologic evidence that long-chain fatty acid transport involves a protein-mediated process. A number of fatty acid transport proteins have been identified, and for unknown reasons, some of these are co-expressed in the same tissues. In muscle and heart FAT/CD36 and FABPpm appear to be key transporters. Both proteins are regulated acutely (within minutes) and chronically (hours to days) by selected physiologic stimuli (insulin, AMP kinase activation). Acute regulation involves the translocation of FAT/CD36 by insulin, muscle contraction and AMP kinase activation, while FABPpm is induced to translocate by muscle contraction and AMP kinase activation, but not by insulin. Protein expression of FAT/CD36 and FABPpm is regulated by prolonged AMP kinase activation (heart) or increased muscle contraction. Prolonged insulin exposure increases the expression of FAT/CD36 but not FABPpm. Trafficking of fatty acid transporters between an intracellular compartment(s) and the plasma membrane is altered in insulin-resistant skeletal muscle, as some FAT/CD36 is permanently relocated to plasma membrane, thereby contributing to insulin resistance due to the increased influx of fatty acids into muscle cells. Studies in FAT/CD36 null mice have revealed that this transporter is key to regulating the increase in the rate of fatty acid metabolism in heart and skeletal muscle. It appears based on a number of experiments that FAT/CD36 and FABPpm may collaborate to increase the rates of fatty acid transport, as these proteins co-immunoprecipitate.

The peripheral circulation and lactic acid metabolism in heart, or cardiovascular, failure.

The peripheral circulation and lactic acid metabolism in heart, or cardiovascular, failure.

Ethanol and protein and amino acid metabolism in heart

Ethanol and protein and amino acid metabolism in heart

Fatty acid metabolism in hearts containing elevated levels of CoA.

Palmitate metabolism was determined in isolated perfused hearts containing elevated levels of coenzyme A (CoA). CoA levels were elevated by perfusing hearts with Krebs-Henseleit buffer containing 0.1 mM cysteine, 0.2 mM dithiothreitol, 15 microM pantothenic acid, and no energy substrate. After 45 min, CoA levels had increased from 537 +/- 14 to 818 +/- 44 nmol/g dry wt. When these hearts containing high CoA were subsequently perfused as working hearts with buffer containing 11 mM glucose and 1.2 mM palmitate, long chain acyl CoA levels increased (94 +/- 5-305 +/- 6 nmol/g dry wt). Oxidation of exogenous palmitate (as measured by 14CO2 production from [U-14C]palmitate) was significantly depressed in hearts containing elevated CoA levels. This apparent reduction in fatty acid oxidation was not due to increased glucose or glycogen utilization. When the concentration of palmitate was decreased to 0.4 mM, acyl CoA levels increased much less, and the apparent rate of [14C]palmitate oxidation was unaffected by elevated CoA. Hearts containing high CoA also incorporated [14C]palmitate into triacylglycerols to a greater extent than did control hearts. To determine whether the apparent decrease in exogenous palmitate oxidation resulted from an increased utilization of unlabeled endogenous triacylglycerol fatty acid, [14C]palmitate specific activity was measured in myocardial acylcarnitine. The specific activity of this pool of fatty acid was similar in both control hearts and hearts containing elevated CoA. Thus dilution of the total cellular [14C]acyl carnitine by triacylglycerol hydrolysis was not sufficient to account for the decrease in [U-14C]palmitate oxidation. The possibility that a small pool of rapidly turning over acyl carnitine becomes dilated is discussed.(ABSTRACT TRUNCATED AT 250 WORDS)