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Heinrich Taegtmeyer

Publications and source records attributed to Heinrich Taegtmeyer.

At least 19 recordsLinked to original sources
PubMed2006

Atrophic remodeling of the transplanted rat heart.

We have previously shown that the common feature of both pressure overload-induced hypertrophy and atrophy is a reactivation of the fetal gene program. Although gene expression profiles and signal transduction pathways in pressure overload hypertrophy have been well studied, little is known about the mechanisms underlying atrophic remodeling of the unloaded heart. Here, we induced atrophic remodeling by heterotopic transplantation of the rat heart. The activity parameters of three signal transduction pathways important in hypertrophy, i.e. mitogen-activated protein (MAP) kinase, mammalian target of rapamycin (mTOR), and Janus kinase/signal transducers and activators of transcription (JAK/STAT), were interrogated. Gene expression of upstream stimuli--insulin-like growth factor 1 (IGF-1) and fibroblast growth factor 2 (FGF-2)--and metabolic correlates, i.e. peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARalpha-regulated genes, of these pathways were also measured. In addition, we measured transcript levels of genes known to regulate skeletal muscle atrophy, all of which are negatively regulated by IGF-1 (Mafbx/Atrogin-1, MuRF-1). Atrophic remodeling of the heart was associated with increased expression of IGF-1 and FGF-2. Transcript levels of the nuclear receptor PPARalpha were decreased, as were the levels of PPARalpha-regulated genes. Furthermore, there was phosphorylation of ERK1, STAT3, and p70S6K with unloading. Consistent with the increase in IGF-1, we found a decrease in Mafbx/Atrogin-1 and MuRF-1 transcript levels. Rapamycin administration at 0.8 mg/kg/day for 7 days resulted in enhanced atrophy and attenuated the phosphorylation of ERK1, STAT3, and p70S6K without altering gene expression. We conclude that there is significant crosstalk between the mTOR, MAP kinase, and JAK/STAT signaling cascades. Furthermore, ubiquitin ligases, known to be essential for skeletal muscle atrophy, decrease in unloading-induced cardiac atrophy.

Animals↗
PubMed2006

Proteome analysis of isolated perfused organ effluent as a novel model for protein biomarker discovery.

The discovery of novel serological biomarkers is critical for improving disease diagnosis and monitoring treatment response. Proteomic analysis of model systems, such as isolated cells in culture and patient plasma and serum, represents the current state-of-the-art. Here, we coupled proteomics with isolated organ perfusion, which allows a disease state to be studied in a physiologic, yet controlled, environment. Potential markers specific to the disease or to changes in the surrounding tissue may be discovered. The effectiveness of this model was evaluated using proteomic analysis of effluent fractions collected from isolated beating rat hearts during reperfusion after brief episodes of ischemia. The detection of clinical markers for myocardial ischemia in this effluent was robust and analytically straightforward, validating the potential of isolated organ perfusion in diagnostic protein discovery.

Animals↗
PubMed2005

Thyroid hormone interacts with PPARalpha and PGC-1 during mitochondrial maturation in sheep heart.

Thyroid hormone (TH) promotes cardiac mitochondrial maturation and substrate metabolism after birth. This regulation involves ligand-dependent binding of nuclear TH receptors to target gene elements. TH also putatively controls genes indirectly by modulating transcription and/or translation of other nuclear steroid receptors and coactivators, such as peroxisome proliferator-activated receptor-alpha (PPARalpha) and peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1). We tested the hypothesis that TH influences PPARalpha and PGC-1 regulation of metabolic genes during postnatal maturation in sheep heart in vivo. We measured their mRNAs and/or protein levels and downstream targets in left ventricle from lambs: fetal (F), 30-day-old after postnatal thyroidectomy (THY), and 30-day-old euthyroid (Con). Both PPARalpha and PGC-1 mRNA expression decreased from F to Con, while PGC-1 protein increased substantially and PPARalpha did not change. THY limited this mRNA response and attenuated the paradoxical postnatal PGC-1 protein elevation but did not alter mRNA levels for PPARalpha, nuclear respiratory factor-1 and hypoxia-inducible factor-1alpha. THY promotion in PPARalpha mRNA did not change PPARalpha protein or mRNA for PPARalpha target genes, pyruvate-dehydrogenase kinase 4 (PDK4) and muscle type carnitine palmitoyltransferase I (mCPTI). THY reduction in PGC-1 protein occurred, while reducing cytochrome c oxidase and cytochrome c content and decreasing cardiac maximal inherent respiratory capacity. These data imply that TH modulates mitochondrial maturation partly through posttranscriptional control of PGC-1, while any important regulation of PDK4 and mCPTI by change in PPARalpha protein expression remains doubtful. Also, the paradoxical expression pattern between mRNA and protein, particularly for PGC-1, suggests a feedback control mechanism.

Animals↗
PubMed2005

Downregulation of peroxisome proliferator-activated receptor-alpha gene expression in a mouse model of ischemic cardiomyopathy is dependent on reactive oxygen species and prevents lipotoxicity.

BACKGROUND: The peroxisome proliferators-activated receptor-alpha (PPARalpha), a transcription factor that modulates fatty acid metabolism, regulates substrate preference in the heart. Although in acute ischemia there is a switch in substrate preference from fatty acids to glucose, metabolic gene expression in repetitive ischemia is not well described. In a mouse model of ischemic cardiomyopathy induced by repetitive ischemia/reperfusion (I/R), we postulated that downregulation of PPARalpha is regulated by reactive oxygen species and is necessary for maintaining contractile function in the heart. METHODS AND RESULTS: Repetitive closed-chest I/R (15 minutes) was performed daily in C57/BL6 mice, mice overexpressing extracellular superoxide dismutase, and mice treated with the PPARalpha agonist-WY-14,643. Echocardiography, histology, and candidate gene expression were measured at 3, 5, 7, and 28 days of repetitive I/R and 15 and 30 days after discontinuation of I/R. Repetitive I/R was associated with a downregulation of PPARalpha-regulated genes and both myosin heavy chain isoform transcript levels, which was reversible on discontinuation of I/R. Overexpression of EC-SOD prevented the downregulation of PPARalpha-regulated genes and myosin iso-genes by repetitive I/R. Furthermore, reactivation of PPARalpha in mice exposed to repetitive I/R worsened contractile function, induced microinfarctions, and increased intramyocardial triglyceride deposition, features suggestive of cardiac lipotoxicity. CONCLUSIONS: Metabolic and myosin isoform gene expression in repetitive I/R is mediated by reactive oxygen species. Furthermore, we suggest that downregulation of PPARalpha in repetitive I/R is an adaptive mechanism that is able to prevent lipotoxicity in the ischemic myocardium.

Animals↗
PubMed2005

Activation of PPARgamma enhances myocardial glucose oxidation and improves contractile function in isolated working hearts of ZDF rats.

It is suggested that insulin resistance and metabolic maladaptation of the heart are causes of contractile dysfunction. We tested the hypothesis whether systemic PPARgamma activation, by changing the metabolic profile in a model of insulin resistance and type 2 diabetes (the ZDF rat) in vivo, improves contractile function of the heart in vitro. Male Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats, at 53-56 days of age, were treated with either GI-262570 (a nonthiazolidinedione PPARgamma agonist; A) or vehicle (V) for 1 wk. Agonist treatment resulted in correction of hyperglycemia and dyslipidemia, as well as in reduced hyperinsulinemia. The accumulation of triacylglycerols in the myocardium, characteristic of the ZDF rat, disappeared with treatment. Cardiac power and rates of glucose oxidation in the isolated working heart were significantly reduced in ZDF-V rats, but both parameters increased to nondiabetic levels with agonist treatment. In ZDF-V hearts, transcript levels of PPARalpha-regulated genes and of myosin heavy chain-beta were upregulated, whereas GLUT4 was downregulated compared with ZL. Agonist treatment of ZDF rats reduced PPARalpha-regulated genes and increased transcripts of GLUT4 and GLUT1. In conclusion, by changing the metabolic profile, reducing myocardial lipid accumulation, and promoting the downregulation of PPARalpha-regulated genes, PPARgamma activation leads to an increased capacity of the myocardium to oxidize glucose and to a tighter coupling of oxidative metabolism and contraction in the setting of insulin resistance and type 2 diabetes.

Adaptation, Physiological↗
PubMed2005

The FOXO3a transcription factor regulates cardiac myocyte size downstream of AKT signaling.

Although signaling mechanisms inducing cardiac hypertrophy have been extensively studied, little is known about the mechanisms that reverse cardiac hypertrophy. Here, we describe the existence of a similar Akt/forkhead signaling axis in cardiac myocytes in vitro and in vivo, which is regulated by insulin, insulin-like growth factor (IGF), stretch, pressure overload, and angiotensin II stimulation. FOXO3a gene transfer prevented both IGF and stretch-induced hypertrophy in rat neonatal cardiac myocyte cultures in vitro. Transduction with FOXO3a also caused a significant reduction in cardiomyocyte size in mouse hearts in vivo. Akt/FOXO signaling regulated the expression of multiple atrophy-related genes "atrogenes," including the ubiquitin ligase atrogin-1 (MAFbx). In cardiac myocyte cultures, transduction with constitutively active Akt or treatment with IGF suppressed atrogin-1 mRNA expression, whereas transduction with FOXO3a stimulated its expression. FOXO3a transduction activated the atrogin-1 promoter in both cultured myocytes and mouse heart. Thus, in cardiomyocytes, as in skeletal muscle, FOXO3a activates an atrogene transcriptional program, which retards or prevents hypertrophy and is down-regulated by multiple physiological and pathological stimuli of myocyte growth.

Angiotensin II↗
PubMed2005

Acclimatization to chronic hypobaric hypoxia is associated with a differential transcriptional profile between the right and left ventricle.

Acute hypobaric hypoxia induces a transient reactivation of the fetal-metabolic gene program in the rat heart. Although chronic hypobaric hypoxia causes alterations in metabolism and cardiac function, little is known about the transcriptional profile associated with acclimatization to chronic hypoxia. Because in chronic hypoxia only the right ventricle is exposed to pressure overload (pulmonary hypertension), we hypothesized that chronic hypobaric hypoxia induces a differential transcriptional profile in the right and left ventricle. Male Wistar rats were exposed to a hypobaric environment (11% O2) for 4, 10, and 12 weeks. Right and left ventricular tissue was isolated for histology and candidate gene expression. Chronic hypobaric hypoxia induced right ventricular hypertrophy without fibrosis. In the right ventricle, changes in metabolic gene expression suggested a downregulation of fatty acid metabolism and an increase in glucose metabolism, while left ventricular metabolic gene expression suggested restoration of fatty acid metabolism. While myosin heavy chain isoform transcript levels in the right ventricle indicated a progressive reactivation of the fetal iso-gene pattern, there was normalization of myosin iso-gene expression in the left ventricle. Similarly, sarcoendoplasmic reticulum ATPase 2a (SERCA2a) transcript levels in the right ventricle decreased by 12 weeks of chronic hypoxia exposure, whereas, left ventricular SERCA2a expression was unchanged. In conclusion, acclimatization to chronic hypobaric hypoxia induced a differential transcriptional response between the right and left ventricle. We speculate that reactivation of the fetal-metabolic program in the right ventricle is adaptive to pressure overload.

Acclimatization↗
PubMed2005

Metabolic energetics and genetics in the heart.

From the first stages of differentiation in the embryo to the end of life, energy substrate metabolism and function are inextricably linked features of the heart. The principle of energy substrate metabolism is simple. For a given developmental stage and for a given environment, the heart oxidizes the most efficient fuel on the path to ATP. The "multitasking" of energy substrate metabolism in the heart entails more than the generation of reducing equivalents for oxidative phosphorylation of ADP in the respiratory chain. In the postnatal heart, substrate switching and metabolic flexibility are features of normal function. In the stressed heart, metabolic remodeling precedes, triggers, and sustains functional and structural remodeling. This manuscript reviews the pleiotropic actions of metabolism in energy transfer, signal transduction, cardiac growth, gene expression, and viability. Examples are presented to illustrate that metabolic signals of stressed and failing heart are the product of complex cellular processes. An early feature of the maladapted heart is a loss of metabolic flexibility. The example of lipotoxic heart failure illustrates the concept of sustained metabolic dysregulation as a cause of contractile dysfunction of the heart. Thus, a paradigm emerges in which metabolic signals not only regulate fluxes through enzyme catalyzed reactions in existing metabolic pathways, but also regulate transcriptional, translational, and post-translational signaling in the heart. As new insights are gained into metabolic adaptation and maladaptation of the heart, metabolic modulation may become an effective strategy for the treatment of heart failure.

Animals↗
PubMed2004

PPAR-gamma agonist rosiglitazone ameliorates ventricular dysfunction in experimental chronic mitral regurgitation.

Previously we reported that the beneficial effects of beta-adrenergic blockade in chronic mitral regurgitation (MR) were in part due to induction of bradycardia, which obviously affects myocardial energy requirements. From this observation we hypothesized that part of the pathophysiology of MR may involve faulty energy substrate utilization, which in turn might lead to potentially harmful lipid accumulation as observed in other models of heart failure. To explore this hypothesis, we measured triglyceride accumulation in the myocardia of dogs with chronic MR and then attempted to enhance myocardial metabolism by chronic administration of the peroxisome proliferator-activated receptor (PPAR)-gamma agonist rosiglitazone. Cardiac tissues were obtained from three groups of dogs that included control animals, dogs with MR for 3 mo without treatment, and dogs with MR for 6 mo that were treated with rosiglitazone (8 mg/day) for the last 3 mo of observation. Hemodynamics and contractile function (end-systolic stress-strain relationship, as measured by K index) were assessed at baseline, 3 mo of MR, and 6 mo of MR (3 mo of the treatment). Lipid accumulation in MR (as indicated by oil red O staining score and TLC analysis) was marked and showed an inverse correlation with the left ventricular (LV) contractility. LV contractility was significantly restored after PPAR therapy (K index: therapy, 3.01 +/- 0.11*; 3 mo MR, 2.12 +/- 0.34; baseline, 4.01 +/- 0.29; ANOVA, P = 0.038; *P < 0.05 vs. 3 mo of MR). At the same time, therapy resulted in a marked reduction of intramyocyte lipid. We conclude that 1) chronic MR leads to intramyocyte myocardial lipid accumulation and contractile dysfunction, and 2) administration of the PPAR-gamma agonist rosiglitazone ameliorates MR-induced LV dysfunction accompanied by a decline in lipid content.

Animals↗
PubMed2004

Nonacute effects of H-FABP deficiency on skeletal muscle glucose uptake in vitro.

Heart-type fatty acid-binding protein (H-FABP) is required for high rates of skeletal muscle long-chain fatty acid (LCFA) oxidation and esterification. Here we assessed whether H-FABP affects soleus muscle glucose uptake when measured in vitro in the absence of LCFA. Wild-type and H-FABP null mice were fed a standard chow or high-fat diet before muscle isolation. With the chow, the mutation increased insulin-dependent deoxyglucose uptake by 141% (P < 0.01) at 0.02 mU/ml of insulin but did not cause a significant effect at 2 mU/ml of insulin; skeletal muscle triglyceride and long-chain acyl-CoA (LCA-CoA) levels remained normal. With the high-fat diet, the mutation increased insulin-dependent deoxyglucose uptake by 190% (P < 0.01) at 2 mU/ml of insulin, thus partially preventing insulin resistance, and it completely prevented the threefold (P < 0.001) diet-induced increase of muscle triglyceride levels; however, muscle LCA-CoA levels showed little or no reduction. With both diets, the mutation reduced the basal (insulin-independent) soleus muscle deoxyglucose uptake by 28% (P < 0.05). These results establish a close relation between FABP-dependent lipid pools and insulin sensitivity and indicate the existence of a nonacute, antagonistic, and H-FABP-dependent fatty acid regulation of basal and insulin-dependent muscle glucose uptake.

Acyl Coenzyme A↗
PubMed2004

Reversal of glucose-insulin-potassium-induced hyperglycemia by aggressive insulin treatment in postoperative heart failure. An observational study.

Metabolic support with glucose-insulin-potassium (GIK) significantly reduces the morbidity and mortality of patients in cardiogenic shock after hypothermic ischemic arrest for aortocoronary bypass surgery. However, a small subset of these patients develops postoperative insulin resistance regardless of their preoperative diabetic status. Whether GIK directly contributes to higher mortality in these patients is unknown. We reviewed the records of 322 patients whose treatment for postoperative cardiogenic shock included GIK. Ten patients (3%) had postoperative hyperglycemia (serum glucose > or =250 mg/dl or 13.9 mmol/l) due to insulin resistance. These were compared to randomly selected GIK-treated, insulin-responsive patients (n = 10) and non-GIK-treated patients (n = 10) for comparison. The insulin-resistant patients required increasing amounts of regular insulin up to 130 U/h until blood glucose levels fell below 250 mg/dl. However, short-term outcomes (IABP support time, length of stay in ICU, 7-day mortality) for insulin- resistant patients were indistinguishable from those for insulin-responsive patients. These data indicate that postoperative iatrogenic hyperglycemia in patients after cardiopulmonary bypass may not be detrimental per se and is reversible when treated with supplemental insulin.

Aged↗
PubMed2004

Hypoxia-induced decrease of UCP3 gene expression in rat heart parallels metabolic gene switching but fails to affect mitochondrial respiratory coupling.

Mitochondrial uncoupling proteins 2 and 3 (UCP2 and UCP3) are postulated to contribute to antioxidant defense, nutrient partitioning, and energy efficiency in the heart. To distinguish isotype function in response to metabolic stress we measured cardiac mitochondrial function and cardiac UCP gene expression following chronic hypobaric hypoxia. Isolated mitochondrial O(2) consumption and ATP synthesis rate were reduced but respiratory coupling was unchanged compared to normoxic groups. Concurrently, left ventricular UCP3 mRNA levels were significantly decreased with hypoxia (p<0.05) while UCP2 levels remained unchanged versus controls. Diminished UCP3 expression was associated with coordinate regulation of counter-regulatory metabolic genes. From these data, we propose a role for UCP3 in the regulation of fatty acid oxidation in the heart as opposed to uncoupling of mitochondria. Moreover, the divergent hypoxia-induced regulation of UCP2 and UCP3 supports distinct mitochondrial regulatory functions of these inner mitochondrial membrane proteins in the heart in response to metabolic stress.

Animals↗