Endocrine Influence on Cardiac Metabolism in Development and Regeneration

Endocrinology ◽  
2021 ◽  
Author(s):  
Niall Graham ◽  
Guo N Huang
Keyword(s):  
Thyroid Hormone ◽  
Fetal Heart ◽  
Cardiac Regeneration ◽  
Cardiac Metabolism ◽  
Proliferative Potential ◽  
Hormonal Status ◽  
Anaerobic Glycolysis ◽  
Functional Maturation ◽  
Metabolic Remodeling ◽  
Endocrine Influence

Abstract Mammalian cardiomyocytes mostly utilize oxidation of fatty acids to generate ATP. The fetal heart, in stark contrast, mostly uses anaerobic glycolysis. During perinatal development, thyroid hormone drives extensive metabolic remodeling in the heart for adaptation to extrauterine life. These changes coincide with critical functional maturation and exit of the cell cycle, making the heart a post-mitotic organ. Here, we review the current understanding on the perinatal shift in metabolism, hormonal status, and proliferative potential in cardiomyocytes. Thyroid hormone and glucocorticoids have roles in adult cardiac metabolism, and both pathways have been implicated as regulators of myocardial regeneration. We discuss the evidence that suggests these processes could be inter-related and how this can help explain variation in cardiac regeneration across ontogeny and phylogeny, and what breakthroughs are still to be made.

Thyroid hormone controls myocardial substrate metabolism through nuclear receptor-mediated and rapid posttranscriptional mechanisms

2006 ◽  
Vol 290 (2) ◽  
pp. E372-E379 ◽  
Author(s):  
Outi M. Hyyti ◽  
Xue-Han Ning ◽  
Norman E. Buroker ◽  
Ming Ge ◽  
Michael A. Portman
Keyword(s):  
Thyroid Hormone ◽  
Cardiac Metabolism ◽  
Pyruvate Dehydrogenase Kinase ◽  
Isolated Hearts ◽  
Myocardial Substrate ◽  
Carnitine Palmitoyltransferase I ◽  
Rapid Modulation ◽  
Cpt I ◽  
The Individual ◽  
C Nmr

Thyroid hormone regulates metabolism through transcriptional and posttranscriptional mechanisms. The integration of these mechanisms in heart is poorly understood. Therefore, we investigated control of substrate flux into the citric acid cycle (CAC) by thyroid hormone using retrogradely perfused isolated hearts ( n = 20) from control (C) and age-matched thyroidectomized rats (T). We determined substrate flux and fractional contributions (Fc) to the CAC by 13C-NMR spectroscopy and isotopomer analyses in hearts perfused with [1,3-13C]acetoacetic acid (0.17 mM), l-[3-13C]lactic acid (LAC, 1.2 mM), [U-13C]long-chain mixed free fatty acids (FFA, 0.35 mM), and unlabeled glucose. Some T hearts were supplied triiodothyronine (T3, 10 nM; TT) for 60 min. Prolonged hypothyroid state reduced myocardial oxygen consumption, although T3 produced no significant change. Hypothyroidism reduced overall CACflux but selectively altered only FFAflux among the individual substrates, though LACflux trended upward. T3 rapidly decreased lactate Fc and flux. 13C labeling of glutamine through glutamate was increased in T with further enhancement in TT. The glutamate-to-glutamine ratio was significantly lower in T and TT. Immunoblots detected a decrease in hypothyroid hearts for muscle carnitine palmitoyltransferase I (CPT I) and a marked increase in pyruvate dehydrogenase kinase (PDK)-2 with no changes in liver CPT I, PDK-4, or hexokinase 2. TT, but not T, displayed elevated glutamine synthetase (GS) expression. These studies showed that T3 regulates cardiac metabolism through integration of several mechanisms, including changes in oxidative enzyme content and rapid modulation of individual substrates fluxes. T3 also moderates forward glutamine flux, possibly by increasing the overall activity of GS.

scholarly journals Metabonomics Analysis of Myocardial Metabolic Dysfunction in Patients with Cardiac Natriuretic Peptide Resistance

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Pan Chang ◽  
Shengping Lei ◽  
Xiaomeng Zhang ◽  
Jing Zhang ◽  
Xihui Wang ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Heart Function ◽  
Biological Marker ◽  
Cyclic Guanosine Monophosphate ◽  
Cardiac Metabolism ◽  
Guanosine Monophosphate ◽  
Enzyme Linked Immunosorbent Assay ◽  
Liquid Chromatograph ◽  
Cardiac Functions ◽  
Metabolic Remodeling

Brain natriuretic peptide (BNP) is an important biological marker and regulator of cardiac function. BNP resistance is characterized by high concentrations of less functionally effective BNP and common in heart failure (HF) patients. However, the roles and consequences of BNP resistance remain poorly understood. Investigate the effects of cardiac BNP resistance and identify potential metabolic biomarkers for screening and diagnosis. Thirty patients and thirty healthy subjects were enrolled in this study. Cardiac functions were evaluated by echocardiography. The plasma levels of cyclic guanosine monophosphate (cGMP) and BNP were measured by enzyme-linked immunosorbent assay (ELISA) and the cGMP/BNP ratio is calculated to determine cardiac natriuretic peptide resistance. Liquid chromatograph tandem mass spectrometry (LC-MS) based untargeted metabolomics analysis was applied to screen metabolic changes. The cGMP/BNP ratio was markedly lower in HF patients than controls. The cGMP/BNP ratio and ejection fraction (EF) were strongly correlated (R2 = 0.676, P < 0.05 ). Importantly, metabolic profiles were substantially different between HF patients and healthy controls. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that the differentially expressed metabolites are involved in signaling pathways that regulate cardiac functions. In HF patients, BNP resistance develops in association with a reduction in heart function and metabolic remodeling. It suggests possible functional roles of BNP resistance in the regulation of cardiac metabolism.

scholarly journals Tissue Distribution and Cardiac Metabolism of 3-Iodothyronamine

Endocrinology ◽  
2010 ◽  
Vol 151 (10) ◽  
pp. 5063-5073 ◽  
Author(s):  
Alessandro Saba ◽  
Grazia Chiellini ◽  
Sabina Frascarelli ◽  
Maja Marchini ◽  
Sandra Ghelardoni ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Amine Oxidase ◽  
Cardiac Metabolism ◽  
Rat Serum ◽  
Rat Hearts ◽  
H9c2 Cardiomyocytes ◽  
Perfused Rat Hearts ◽  
First Time ◽  
G Protein Coupled ◽  
Isolated Perfused Rat Hearts

3-Iodothyronamine (T1AM) is a novel relative of thyroid hormone, able to interact with specific G protein-coupled receptors, known as trace amine-associated receptors. Significant functional effects are produced by exogenous T1AM, including a negative inotropic and chronotropic effect in cardiac preparations. This work was aimed at estimating endogenous T1AM concentration in different tissues and determining its cardiac metabolism. A novel HPLC tandem mass spectrometry assay was developed, allowing detection of T1AM, thyronamine, 3-iodothyroacetic acid, and thyroacetic acid. T1AM was detected in rat serum, at the concentration of 0.3 ± 0.03 pmol/ml, and in all tested organs (heart, liver, kidney, skeletal muscle, stomach, lung, and brain), at concentrations significantly higher than the serum concentration, ranging from 5.6 ± 1.5 pmol/g in lung to 92.9 ± 28.5 pmol/g in liver. T1AM was also identified for the first time in human blood. In H9c2 cardiomyocytes and isolated perfused rat hearts, significant Na+-dependent uptake of exogenous T1AM was observed, and at the steady state total cellular or tissue T1AM concentration exceeded extracellular concentration by more than 20-fold. In both preparations T1AM underwent oxidative deamination to 3-iodothyroacetic acid. T1AM deamination was inhibited by iproniazid but not pargyline or semicarbazide, suggesting the involvement of both monoamine oxidase and semicarbazide-sensitive amine oxidase. Thyronamine and thyroacetic acid were not detected in heart. Finally, evidence of T1AM production was observed in cardiomyocytes exposed to exogenous thyroid hormone, although the activity of this pathway was very low.

scholarly journals Metabolic reprogramming via PPARα signaling in cardiac hypertrophy and failure: From metabolomics to epigenetics

2017 ◽  
Vol 313 (3) ◽  
pp. H584-H596 ◽  
Author(s):  
Junco Shibayama Warren ◽  
Shin-ichi Oka ◽  
Daniela Zablocki ◽  
Junichi Sadoshima
Keyword(s):  
Cardiac Hypertrophy ◽  
Current Knowledge ◽  
Critical Role ◽  
Cardiac Metabolism ◽  
Metabolic Reprogramming ◽  
Metabolic Phenotype ◽  
Global Changes ◽  
Peroxisome Proliferator ◽  
Metabolic Remodeling

Studies using omics-based approaches have advanced our knowledge of metabolic remodeling in cardiac hypertrophy and failure. Metabolomic analysis of the failing heart has revealed global changes in mitochondrial substrate metabolism. Peroxisome proliferator-activated receptor-α (PPARα) plays a critical role in synergistic regulation of cardiac metabolism through transcriptional control. Metabolic reprogramming via PPARα signaling in heart failure ultimately propagates into myocardial energetics. However, emerging evidence suggests that the expression level of PPARα per se does not always explain the energetic state in the heart. The transcriptional activities of PPARα are dynamic, yet highly coordinated. An additional level of complexity in the PPARα regulatory mechanism arises from its ability to interact with various partners, which ultimately determines the metabolic phenotype of the diseased heart. This review summarizes our current knowledge of the PPARα regulatory mechanisms in cardiac metabolism and the possible role of PPARα in epigenetic modifications in the diseased heart. In addition, we discuss how metabolomics can contribute to a better understanding of the role of PPARα in the progression of cardiac hypertrophy and failure.

scholarly journals Hormonal control of cardiac regenerative potential

2020 ◽  
Author(s):  
Alexander V. Amram ◽  
Stephen Cutie ◽  
Guo N. Huang
Keyword(s):  
Vitamin D ◽  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Cardiac Regeneration ◽  
Postnatal Period ◽  
Hormonal Control ◽  
Model Systems ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Endocrine Signaling

Research conducted across phylogeny on cardiac regenerative responses following heart injury implicates endocrine signaling as a pivotal regulator of both cardiomyocyte proliferation and heart regeneration. Three prominently studied endocrine factors are thyroid hormone, vitamin D, and glucocorticoids, which canonically regulate gene expression through their respective nuclear receptors thyroid hormone receptor, vitamin D receptor, and glucocorticoid receptor. The main animal model systems of interest include humans, mice, and zebrafish, which vary in cardiac regenerative responses possibly due to the differential onsets and intensities of endocrine signaling levels throughout their embryonic to postnatal organismal development. Zebrafish and lower vertebrates tend to retain robust cardiac regenerative capacity into adulthood while mice and other higher vertebrates experience greatly diminished cardiac regenerative potential in their initial postnatal period that is sustained throughout adulthood. Here, we review recent progress in understanding how these three endocrine signaling pathways regulate cardiomyocyte proliferation and heart regeneration with a particular focus on the controversial findings that may arise from different assays, cellular-context, age, and species. Further investigating the role of each endocrine nuclear receptor in cardiac regeneration from an evolutionary perspective enables comparative studies between species in hopes of extrapolating the findings to novel therapies for human cardiovascular disease.

scholarly journals Stable Isotopes for Tracing Cardiac Metabolism in Diseases

2021 ◽  
Vol 8 ◽  
Author(s):  
Anja Karlstaedt
Keyword(s):  
Cardiovascular Disease ◽  
Stable Isotope ◽  
Isotope Labeling ◽  
Contractile Function ◽  
Ex Vivo ◽  
Cardiac Metabolism ◽  
Metabolic Adaptation ◽  
Cardiovascular Research ◽  
Metabolic Remodeling

Although metabolic remodeling during cardiovascular diseases has been well-recognized for decades, the recent development of analytical platforms and mathematical tools has driven the emergence of assessing cardiac metabolism using tracers. Metabolism is a critical component of cellular functions and adaptation to stress. The pathogenesis of cardiovascular disease involves metabolic adaptation to maintain cardiac contractile function even in advanced disease stages. Stable-isotope tracer measurements are a powerful tool for measuring flux distributions at the whole organism level and assessing metabolic changes at a systems level in vivo. The goal of this review is to summarize techniques and concepts for in vivo or ex vivo stable isotope labeling in cardiovascular research, to highlight mathematical concepts and their limitations, to describe analytical methods at the tissue and single-cell level, and to discuss opportunities to leverage metabolic models to address important mechanistic questions relevant to all patients with cardiovascular disease.

Advances in heart regeneration based on cardiomyocyte proliferation and regenerative potential of binucleated cardiomyocytes and polyploidization

2019 ◽  
Vol 133 (11) ◽  
pp. 1229-1253 ◽  
Author(s):  
Marina Leone ◽  
Felix B. Engel
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Relevant Literature ◽  
Cardiac Regeneration ◽  
Coronary Intervention ◽  
Cell Types ◽  
Proliferative Potential ◽  
Cardiomyocyte Proliferation ◽  
Post Injury ◽  
Great Achievement

Abstract One great achievement in medical practice is the reduction in acute mortality of myocardial infarction due to identifying risk factors, antiplatelet therapy, optimized hospitalization and acute percutaneous coronary intervention. Yet, the prevalence of heart failure is increasing presenting a major socio-economic burden. Thus, there is a great need for novel therapies that can reverse damage inflicted to the heart. In recent years, data have accumulated suggesting that induction of cardiomyocyte proliferation might be a future option for cardiac regeneration. Here, we review the relevant literature since September 2015 concluding that it remains a challenge to verify that a therapy induces indeed cardiomyocyte proliferation. Most importantly, it is unclear that the detected increase in cardiomyocyte cell cycle activity is required for an associated improved function. In addition, we review the literature regarding the evidence that binucleated and polyploid mononucleated cardiomyocytes can divide, and put this in context to other cell types. Our analysis shows that there is significant evidence that binucleated cardiomyocytes can divide. Yet, it remains elusive whether also polyploid mononucleated cardiomyocytes can divide, how efficient proliferation of binucleated cardiomyocytes can be induced, what mechanism regulates cell cycle progression in these cells, and what fate and physiological properties the daughter cells have. In summary, we propose to standardize and independently validate cardiac regeneration studies, encourage the field to study the proliferative potential of binucleated and polyploid mononucleated cardiomyocytes, and to determine whether induction of polyploidization can enhance cardiac function post-injury.

Abstract 333: MED13-dependent Regulation of Cardiac Thyroid Hormone Signaling

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Rachel Minerath ◽  
Ines Martins ◽  
Chad Grueter
Keyword(s):  
Thyroid Hormone ◽  
Molecular Mechanisms ◽  
Cardiac Contractility ◽  
Cardiac Metabolism ◽  
Heart Weight ◽  
Chow Diet ◽  
Basal Transcriptional Machinery ◽  
Complex Protein ◽  
Normal Chow

Thyroid hormone (TH) is a key regulator of cardiac metabolism. While hypothyroidism is known to result in adverse cardiac effects, the molecular mechanisms that modulate TH signaling are not completely understood. Mediator is a multiprotein complex that coordinates signal dependent transcription factors with basal transcriptional machinery. Mediator complex protein, MED13, was previously demonstrated to repress numerous thyroid receptor (TR) response genes in the heart. Furthermore, we have previously demonstrated that mice overexpressing cardiac MED13 (MED13cTg) treated with propylthiouracil (PTU), an inhibitor of T3 biosynthesis, were resistant to PTU-dependent decreases in cardiac contractility. Here we demonstrate that MED13 expression is induced in the hearts of mice in response to a PTU diet. To elucidate the role of MED13 in transcriptional regulation of cardiac TH signaling, cardiac-specific Med13 knockout mice (MED13cKO) and control mice were placed on a PTU diet or normal chow diet for 4 weeks. An additional group of mice on PTU diet were treated acutely with thyroid hormone (T3). While heart weight to body weight ratios did not differ between genotypes, RNA sequencing was performed from hearts of these mice to understand the role of MED13 in TR-dependent transcription. Echocardiography was performed to assess cardiac function in these mice. In addition, histology was performed to evaluate cardiac structure and fibrosis. These studies demonstrate that MED13 is induced in response to hypothyroidism and further deciphers molecular mechanisms of MED13 regulation of TR-dependent transcription.

scholarly journals Detrimental effects of thyroid hormone analog DITPA in the mouse heart: increased mortality with in vivo acute myocardial ischemia-reperfusion

2011 ◽  
Vol 300 (2) ◽  
pp. H702-H711 ◽  
Author(s):  
M. A. Hassan Talukder ◽  
Fuchun Yang ◽  
Yoshinori Nishijima ◽  
Chun-An Chen ◽  
Lin Xie ◽  
...  
Keyword(s):  
Heart Rate ◽  
Thyroid Hormone ◽  
Myocardial Ischemia ◽  
Contractile Function ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Cardiac Metabolism ◽  
Mouse Heart ◽  
Myocardial Ischemia Reperfusion

There is emerging evidence that treatment with thyroid hormone (TH) can improve postischemic cardiac function. 3,5-Diiodothyropropionic acid (DITPA), a TH analog, has been proposed to be a safer therapeutic agent than TH because of its negligible effects on cardiac metabolism and heart rate. However, conflicting results have been reported for the cardiac effects of DITPA. Importantly, recent clinical trials demonstrated no symptomatic benefit in patients with DITPA despite some improved hemodynamic and metabolic parameters. To address these issues, dose-dependent effects of DITPA were investigated in mice for baseline cardiovascular effects and postischemic myocardial function and/or salvage. Mice were treated with subcutaneous DITPA at 0.937, 1.875, 3.75, or 7.5 mg·kg−1·day−1 for 7 days, and the results were compared with untreated mice for ex vivo and/or in vivo myocardial ischemia-reperfusion (I/R). DITPA had no effects on baseline body temperature, body weight, or heart rate; however, it mildly increased blood pressure. In isolated hearts, baseline contractile function was significantly impaired in DITPA-pretreated mice; however, postischemic recovery was comparable between untreated and DITPA-treated groups. In vivo baseline cardiac parameters were significantly affected by DITPA, with increased ventricular dimensions and decreased contractile function. Importantly, DITPA-treated mice demonstrated high prevalence of fatal cardiac rhythm abnormalities during in vivo ischemia and/or reperfusion. There were no improvements in myocardial infarction and postischemic fractional shortening with DITPA. Myocardial sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), phospholamban (PLB), and heat shock protein (HSP) levels remained unchanged with DITPA treatment. Thus DITPA administration impairs baseline cardiac parameters in mice and can be fatal during in vivo acute myocardial I/R.

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