Fatty acids and phospholipids of adult and newborn rat hearts and of cultured, beating neonatal rat myocardial cells

Rogers, Cheryl

doi:10.1007/bf02532502

Cited by 32 publications

(8 citation statements)

References 27 publications

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“…Choice of the fatty acids was predicated upon the different cellular and metabolic roles they have: Palmitate and heptadecanoate readily undergo / 3 oxidation, but arachidonate oxidation by myocytes is relatively slight (Hohl and Rosen, 1987). Palmitate and arachidonate, but not heptadecanoate, are major fatty acids esterified to myocardial membrane phosphoglycerides (Rogers, 1974). Neither TOFA nor its CoA ester enters intermediary metabolism (McCune and Harris, 1979).…”

Section: Resultsmentioning

confidence: 99%

Amphiphile‐induced heart muscle‐cell (Myocyte) injury: Effects of intracellular fatty acid overload

Janero

Burghardt

Feldman

1988

Journal Cellular Physiology

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Lipid amphiphile toxicity may be an important contributor to myocardial injury, especially during ischemia/reperfusion. In order to investigate directly the potential biochemical and metabolic effects of amphiphile overload on the functioning heart muscle cell (myocyte), a novel model of nonesterified fatty acid (NEFA)-induced myocyte damage has been defined. The model uses intact, beating neonatal rat myocytes in primary monolayer culture as a study object and 5-(tetradecyloxy)-2-furoic acid (TOFA) as a nonmetabolizable fatty acid. Myocytes incubated with TOFA accumulated it as NEFA, and the consequent NEFA amphiphile overload elicited a variety of cellular defects (including decreased beating rate, depletion of high-energy stores and glycogen pools, and breakdown of myocyte membrane phospholipid) and culminated in cell death. The amphiphile-induced cellular pathology could be reversed by removing TOFA from the culture medium, which resulted in intracellular TOFA "wash-out." Although the development and severity of amphiphile-induced myocyte injury could be correlated with both the intracellular TOFA/NEFA content (i.e., the level of TOFA to which the cells were exposed) and the duration of this exposure, removal of amphiphile overload did not inevitably lead to myocyte recovery. TOFA had adverse effects on myocyte mitochondrial function in situ (decoupling of oxidative phosphorylation, impairing respiratory control) and on myocyte oxidative catabolism (transiently increasing fatty acid beta oxidation, citric acid cycle flux, and glucose oxidation). The amphiphile-induced bioenergetic abnormalities appeared to constitute a state of "metabolic anoxia" underlying the progression of myocyte injury to cell death. This anoxic state could be ameliorated to some extent, but not prevented, by carbohydrate catabolism.

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Section: Resultsmentioning

confidence: 99%

Amphiphile‐induced heart muscle‐cell (Myocyte) injury: Effects of intracellular fatty acid overload

Janero

Burghardt

Feldman

1988

Journal Cellular Physiology

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“…For example, as shown by den Haan et al [46], cultured NRVM monolayers have a less polarized resting membrane potential (~ −60 mV) than intact adult or neonatal rat hearts (~−80 mV), which could alter the sensitivity of the cultured cells′ electrophysiology to ion channel modulators. In addition, differences in metabolism in adult versus neonatal hearts are well known [47, 48], so while the NRVM monolayer is a practical and useful model to study electrical activity and mitochondrial function during IR, extrapolation of the findings to arrhythmogenic mechanisms in adult hearts should be done with caution. While K ATP current can contribute to arrhythmogenesis in NRVM monolayers after chemical uncoupling of ΔΨ m [28], the present findings suggests that IR induces a unique set of alterations in the electrophysiological substrate, underscoring the utility of the coverslip IR model for mechanistic investigation.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial instability during regional ischemia–reperfusion underlies arrhythmias in monolayers of cardiomyocytes

Solhjoo

O’Rourke

2015

Journal of Molecular and Cellular Cardiology

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Regional depolarization of the mitochondrial network can alter cellular electrical excitability and increase the propensity for reentry, in part, through the opening of sarcolemmal KATP channels. Mitochondrial inner membrane potential (ΔΨm) instability or oscillation can be induced in myocytes by exposure to reactive oxygen species (ROS), laser excitation, or glutathione depletion, and is thought to be a major factor in arrhythmogenesis during ischemia-reperfusion. Nevertheless, the correlation between ΔΨm recovery kinetics and reperfusion-induced arrhythmias has been difficult to demonstrate experimentally. Here, we investigate the relationship between subcellular changes in ΔΨm, cellular glutathione redox potential, electrical excitability, and wave propagation during coverslip-induced ischemia-reperfusion (IR) in neonatal rat ventricular myocyte (NRVM) monolayers. Ischemia led to decreased action potential amplitude and duration followed by electrical inexcitability after ~ 15 min of ischemia. ΔΨm depolarization occurred in two phases during ischemia: in phase 1 (< 30 min ischemia), mitochondrial clusters within individual NRVMs depolarized, while phase 2 ΔΨm depolarization (30–60 min) was characterized by global functional collapse of the mitochondrial network across the whole ischemic region of the monolayer, typically involving a propagating metabolic wave. Oxidation of the glutathione (GSSG:GSH) redox potential occurred during ischemia, followed by recovery upon reperfusion (i.e., lifting the coverslip). ΔΨm recovered in the mitochondria of individual myocytes quite rapidly upon reperfusion (< 5 min), but was highly unstable, characterized by subcellular oscillations or flickering of clusters of mitochondria in NRVMs across the reperfused region. Electrical excitability also recovered in a heterogeneous manner, providing an arrhythmogenic substrate which led to formation of sustained reentry. Treatment with 4′-chlorodiazepam, a peripheral benzodiazepine receptor ligand, prevented ΔΨm oscillation, improved GSH recovery rate, and prevented reentry during reperfusion, indicating that stabilization of mitochondrial network dynamics is an important component of preventing post-ischemic arrhythmias.

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“…In biological systems, oxidative stress carries with it the potential for polyunsaturated fatty acid peroxidation (Janero, 1990a). In heart-muscle tissue, as in the cardiomyocyte, polyunsaturated fatty acids are largely arachidonicacid esters of membrane phospholipid (Rogers, 1974;Janero and Burghardt, 1 9 8 9~) .…”

Section: H20-induced Degenerative Changes To Cardiomyocyte-membrane mentioning

confidence: 99%

Hydrogen peroxide‐induced oxidative stress to the mammalian heart‐muscle cell (cardiomyocyte): Lethal peroxidative membrane injury

Janero¹,

Hreniuk²,

Sharif³

1991

Journal Cellular Physiology

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Oxidative stress induced by hydrogen peroxide (H2O2) may contribute to the pathogenesis of ischemic-reperfusion injury in the heart. For the purpose of investigating directly the injury potential of H2O2 on heart muscle, a cellular model of H2O2-induced myocardial oxidative stress was developed. This model employed primary monolayer cultures of intact, beating neonatal-rat cardiomyocytes and discrete concentrations of reagent H2O2 in defined, supplement-free culture medium. Cardiomyocytes challenged with H2O2 readily metabolized it such that the culture content of H2O2 diminished over time, but was not depleted. The consequent H2O2-induced oxidative stress caused lethal sarcolemmal disruption (as measured by lactate dehydrogenase release), and cardiomyocyte integrity could be preserved by catalase. During oxidative stress, a spectrum of cellular derangements developed, including membrane phospholipid peroxidation, thiol oxidation, consumption of the major chain-breaking membrane antiperoxidant (alpha-tocopherol), and ATP loss. No net change in the protein or phospholipid contents of cardiomyocyte membranes accompanied H2O2-induced oxidative stress, but an increased turnover of these membrane constituents occurred in response to H2O2. Development of lethal cardiomyocyte injury during H2O2-induced oxidative stress did not require the presence of H2O2 itself; a brief "pulse" exposure of the cardiomyocytes to H2O2 was sufficient to incite the pathogenic mechanism leading to cell disruption. Cardiomyocyte disruption was dependent upon an intracellular source of redox-active iron and the iron-dependent transformation of internalized H2O2 into products (e.g., the hydroxyl radical) capable of initiating lipid peroxidation, since iron chelators and hydroxyl-radical scavengers were cytoprotective. The accelerated turnover of cardiomyocyte-membrane protein and phospholipid was inhibited by antiperoxidants, suggesting that the turnover reflected molecular repair of oxidized membrane constitutents. Likewise, the consumption of alpha-tocopherol and the oxidation of cellular thiols appeared to be epiphenomena of peroxidation. Antiperoxidant interventions coordinately abolished both H2O2-induced lipid peroxidation and sarcolemmal disruption, demonstrating that an intimate pathogenic relationship exists between sarcolemmal peroxidation and lethal compromise of cardiomyocyte integrity in response to H2O2-induced oxidative stress. Although sarcolemmal peroxidation was causally related to cardiomyocyte disruption during H2O2-induced oxidative stress, a nonperoxidative route of H2O2 cytotoxicity was also identified, which was expressed in the complete absence of cardiomyocyte-membrane peroxidation. The latter mode of H2O2-induced cardiomyocyte injury involved ATP loss such that membrane peroxidation and cardiomyocyte disruption on the one hand and cellular de-energization on the other could be completely dissociated.(ABSTRACT TRUNCATED AT 400 WORDS)

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Fatty acids and phospholipids of adult and newborn rat hearts and of cultured, beating neonatal rat myocardial cells

Cited by 32 publications

References 27 publications

Amphiphile‐induced heart muscle‐cell (Myocyte) injury: Effects of intracellular fatty acid overload

Amphiphile‐induced heart muscle‐cell (Myocyte) injury: Effects of intracellular fatty acid overload

Mitochondrial instability during regional ischemia–reperfusion underlies arrhythmias in monolayers of cardiomyocytes

Hydrogen peroxide‐induced oxidative stress to the mammalian heart‐muscle cell (cardiomyocyte): Lethal peroxidative membrane injury

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