Metabolic Gene Expression in Fetal and Failing Human Heart

Razeghi, Peter; Young, Martin E.; Alcorn, Joseph L.; Moravec, Christine S.; Frazier, O.H.; Taegtmeyer, Heinrich

doi:10.1161/hc4901.100526

Cited by 541 publications

(458 citation statements)

References 47 publications

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“…This would also be consistent with findings in the failing heart where function can be improved by treatment with FA oxidation inhibitors (45). The failing heart has limited capability to oxidize FA because it has reverted to a fetal metabolic gene profile and depends on glucose utilization for energy (46,47).…”

Section: Discussionsupporting

confidence: 83%

Myocardial recovery from ischemia is impaired in CD36-null mice and restored by myocyte CD36 expression or medium-chain fatty acids

Irie

Krukenkamp

Brinkmann

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Long-chain fatty acid uptake, which provides a large part of myocardial energy, is impaired in human and murine hearts deficient in the membrane fatty acid translocase, FAT͞CD36. We examined myocardial function in CD36-null mice using the working heart. Fatty acid oxidation and stores of glycogen, triglycerides, and ATP were reduced in CD36-deficient hearts and were restored to WT levels by rescue of myocyte CD36. Under normal perfusion conditions, CD36-null hearts had similar cardiac outputs and end-diastolic pressures as WT or transgenic hearts. After 6 min of ischemia, cardiac output decreased by 41% and end diastolic pressure tripled for CD36-null hearts, with no significant changes in WT or transgenic hearts. Null hearts also failed more frequently after ischemia as compared with WT or transgenics. To dissect out contribution of fatty acid uptake, a perfusate-lacking fatty acids was used. This decreased cardiac output after ischemia by 30% in WT hearts as compared with 50% for CD36-deficient hearts. End diastolic pressure, a negative index of myocardial performance, increased after ischemia in all heart types. Addition to the perfusate of a medium-chain fatty acid (caprylic acid) that does not require CD36 for uptake alleviated poor ischemic tolerance of CD36-null hearts. In summary, recovery from ischemia is compromised in CD36-deficient hearts and can be restored by CD36 rescue or by supplying medium-chain fatty acids. It would be important to determine whether the findings apply to the human situation where polymorphisms of the CD36 gene are relatively common.CD36 rescue ͉ working heart ͉ fatty acid oxidation F atty acid (FA) uptake consists of two components, passive diffusion and carrier-mediated transport specific for FA with Ͼ8-10 carbons (1). An 88-kDa glycoprotein, FAT (2), a homolog of human CD36 (3, 4) was implicated in FA transport by labeling with the transport inhibitor sulfo-N-succinimidyl oleate (1, 5). The role of FAT͞CD36 in FA uptake was confirmed by studies of mice with CD36 deficiency or overexpression (6, 7). CD36 is abundant in the heart (2, 8), and its deficiency is associated with a 60-80% decrease in myocardial FA uptake (9, 10) and with a severalfold compensatory increase in glucose utilization (11).There is strong evidence for a critical role of CD36-facilitated FA uptake during muscle contraction, which was shown to recruit the protein to the plasma membrane (12). Muscle-targeted overexpression of CD36 enhanced FA oxidation in response to contraction severalfold (7). In line with this, CD36-null mice (6) perform poorly on treadmill and swimming tests (A.I., unpublished observations). However the impact of CD36 deficiency on the performance of the heart, which relies on FA for energy, remains unknown. Such information may have clinical relevance because incidence of CD36 deficiency in humans ranges between 0.3% and 18.5% depending on the population (13). CD36-deficient humans have a defect in myocardial FA uptake (14, 15) that is similar in magnitude to that observed in the CD36-...

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Section: Discussionsupporting

confidence: 83%

Myocardial recovery from ischemia is impaired in CD36-null mice and restored by myocyte CD36 expression or medium-chain fatty acids

Irie

Krukenkamp

Brinkmann

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…We found a profound reduction of Tfam transcripts (Table 2) confirming efficient disruption of the Tfam gene in knockout hearts. We found reduced expression of sarcoplasmic reticulum Ca 2ϩ ATPase (Serca2) and increased expression of atrial natriuretic factor (Anf) mRNA (data not shown) consistent with our previous results (14) and observations in other heart failure models (26)(27)(28). Several changes in gene expression were compatible with compensation of impaired mitochondrial function, e.g., genes involved in import, synthesis, and turnover of mitochondrial proteins showed increased expression in MS and LS knockouts ( Table 2).…”

Section: Major Alterations In Gene Expression Occur Concomitant With supporting

confidence: 90%

A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts

Hansson

Hance

Dufour

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

203

148

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We performed global gene expression analyses in mouse hearts with progressive respiratory chain deficiency and found a metabolic switch at an early disease stage. The tissue-specific mitochondrial transcription factor A (Tfam) knockout mice of this study displayed a progressive heart phenotype with depletion of mtDNA and an accompanying severe decline of respiratory chain enzyme activities along with a decreased mitochondrial ATP production rate. These characteristics were observed after 2 weeks of age and became gradually more severe until the terminal stage occurred at 10 -12 weeks of age. Global gene expression analyses with microarrays showed that a metabolic switch occurred early in the progression of cardiac mitochondrial dysfunction. A large number of genes encoding critical enzymes in fatty acid oxidation showed decreased expression whereas several genes encoding glycolytic enzymes showed increased expression. These alterations are consistent with activation of a fetal gene expression program, a well-documented phenomenon in cardiac disease. An increase in mitochondrial mass was not observed until the disease had reached an advanced stage. In contrast to what we have earlier observed in respiratory chain-deficient skeletal muscle, the increased mitochondrial biogenesis in respiratory chain-deficient heart muscle did not increase the overall mitochondrial ATP production rate. The observed switch in metabolism is unlikely to benefit energy homeostasis in the respiratory chain-deficient hearts and therefore likely aggravates the disease. It can thus be concluded that at least some of the secondary gene expression alterations in mitochondrial cardiomyopathy do not compensate but rather directly contribute to heart failure progression.

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“…13 Moreover, an extensive body of experimental studies has revealed altered expression of metabolic genes, proteins and metabolites that contribute to cardiovascular disease (CVD), including ischemia-reperfusion injury, cardiac remodeling and heart failure. 8,14 The ability to probe alterations in cardiac energetics non-invasively, and in real time, may improve our understanding of the pathogenesis of CVD and improve patient care.…”

mentioning

confidence: 99%

Probing the cardiac malate–aspartate shuttle non‐invasively using hyperpolarized [1,2‐¹³C₂]pyruvate

Chen

Lau

et al. 2017

NMR in Biomedicine

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Previous studies have demonstrated that using hyperpolarized [2-13 C]pyruvate as a contrast agent can reveal 13 C signals from metabolites associated with the tricarboxylic acid (TCA) cycle.However, the metabolites detectable from TCA cycle-mediated oxidation of [2-13 C]pyruvate are the result of several metabolic steps. In the instance of the [5-13 C]glutamate signal, the amplitude can be modulated by changes to the rates of pyruvate dehydrogenase (PDH) flux, TCA cycle flux and metabolite pool size. Also key is the malate-aspartate shuttle, which facilitates the transport of cytosolic reducing equivalents into the mitochondria for oxidation via the malate-α-ketoglutarate transporter, a process coupled to the exchange of cytosolic malate for mitochondrial α-ketoglutarate. In this study, we investigated the mechanism driving the observed changes to hyperpolarized [2-13 C]pyruvate metabolism. Using hyperpolarized [1,2-13 C]pyruvate with magnetic resonance spectroscopy (MRS) in the porcine heart with different workloads, it was possible to probe 13 C-glutamate labeling relative to rates of cytosolic metabolism, PDH flux and TCA cycle turnover in a single experiment non-invasively. Via the [1-13 C]pyruvate label, we observed more than a five-fold increase in the cytosolic conversion of pyruvate to [1-13 C]lactate and [1-13 C]alanine with higher workload. 13 C-Bicarbonate production by PDH was increased by a factor of 2.2. Cardiac cine imaging measured a two-fold increase in cardiac output, which is known to couple to TCA cycle turnover. Via the [2-13 C]pyruvate label, we observed that 13 C-acetylcarnitine production increased 2.5-fold in proportion to the 13 C-bicarbonate signal, whereas the 13 C-glutamate metabolic flux remained constant on adrenergic activation. Thus, the 13 C-glutamate signal relative to the amount of 13 C-labeled acetyl-coenzyme A (acetylCoA) entering the TCA cycle was decreased by 40%. The data strongly suggest that NADH (reduced form of nicotinamide adenine dinucleotide) shuttling from the cytosol to the mitochondria via the malate-aspartate shuttle is limited on adrenergic activation. Changes in [5-13 C]glutamate production from [2-13 C]pyruvate may play an important future role in non-invasive myocardial assessment in patients with cardiovascular diseases, but careful interpretation of the results is required.

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Metabolic Gene Expression in Fetal and Failing Human Heart

Cited by 541 publications

References 47 publications

Myocardial recovery from ischemia is impaired in CD36-null mice and restored by myocyte CD36 expression or medium-chain fatty acids

Myocardial recovery from ischemia is impaired in CD36-null mice and restored by myocyte CD36 expression or medium-chain fatty acids

A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts

Probing the cardiac malate–aspartate shuttle non‐invasively using hyperpolarized [1,2‐¹³C₂]pyruvate

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Metabolic Gene Expression in Fetal and Failing Human Heart

Cited by 541 publications

References 47 publications

Myocardial recovery from ischemia is impaired in CD36-null mice and restored by myocyte CD36 expression or medium-chain fatty acids

Myocardial recovery from ischemia is impaired in CD36-null mice and restored by myocyte CD36 expression or medium-chain fatty acids

A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts

Probing the cardiac malate–aspartate shuttle non‐invasively using hyperpolarized [1,2‐13C2]pyruvate

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Probing the cardiac malate–aspartate shuttle non‐invasively using hyperpolarized [1,2‐¹³C₂]pyruvate