Comparative toxicity of allylamine and acrolein in cultured myocytes and fibroblasts from neonatal rat heart

Toraason, Mark; Luken, Mary E.; Breitenstein, Michael; Krueger, John A.; Biagini, Raymond E.

doi:10.1016/0300-483x(89)90216-3

Cited by 97 publications

(32 citation statements)

References 17 publications

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“…NRVMs were isolated using a standard isolation system (Worthington Biochemical Corporation) (83). Hearts from 1- to 2-day-old Sprague Dawley rats were harvested and minced in calcium- and magnesium-free HBSS, and the tissue was digested with 50 μg/ml trypsin at 4°C for 20 to 24 hours.…”

Section: Experimental Studiesmentioning

confidence: 99%

FGF23 induces left ventricular hypertrophy

Faul¹,

Amaral²,

Oskouei³

et al. 2011

J. Clin. Invest.

1,787

1,807

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Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.

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Section: Experimental Studiesmentioning

confidence: 99%

FGF23 induces left ventricular hypertrophy

Faul¹,

Amaral²,

Oskouei³

et al. 2011

J. Clin. Invest.

1,787

1,807

View full text Add to dashboard Cite

show abstract

“…The isolation and culturing of neonatal mouse ventricular cardiomyocytes were performed from 3-day-old C57BL/6J mice pups, according to a modified protocol (56). Briefly, excised mouse ventricles were washed in Ca 2ϩ and Mg 2ϩ free Hank's balanced salt solution (HBSS), pH 7.4, (in g/l) 0.4 KCl, 0.06 KH2PO4, 8.0 NaCl, and 0.05 Na2HPO4, and minced into small pieces on ice.…”

Section: Cell Culturementioning

confidence: 99%

The role of frataxin in doxorubicin-mediated cardiac hypertrophy

Mouli

Nanayakkara

AlAlasmari

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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(DOX) is a highly effective anti-neoplastic agent; however, its cumulative dosing schedules are clinically limited by the development of cardiotoxicity. Previous studies have attributed the cause of DOXmediated cardiotoxicity to mitochondrial iron accumulation and the ensuing reactive oxygen species (ROS) formation. The present study investigates the role of frataxin (FXN), a mitochondrial iron-sulfur biogenesis protein, and its role in development of DOX-mediated mitochondrial dysfunction. Athymic mice treated with DOX (5 mg/ kg, 1 dose/wk with treatments, followed by 2-wk recovery) displayed left ventricular hypertrophy, as observed by impaired cardiac hemodynamic performance parameters. Furthermore, we also observed significant reduction in FXN expression in DOX-treated animals and H9C2 cardiomyoblast cell lines, resulting in increased mitochondrial iron accumulation and the ensuing ROS formation. This observation was paralleled in DOX-treated H9C2 cells by a significant reduction in the mitochondrial bioenergetics, as observed by the reduction of myocardial energy regulation. Surprisingly, similar results were observed in our FXN knockdown stable cell lines constructed by lentiviral technology using short hairpin RNA. To better understand the cardioprotective role of FXN against DOX, we constructed FXN overexpressing cardiomyoblasts, which displayed cardioprotection against mitochondrial iron accumulation, ROS formation, and reduction of mitochondrial bioenergetics. Lastly, our FXN overexpressing cardiomyoblasts were protected from DOX-mediated cardiac hypertrophy. Together, our findings reveal novel insights into the development of DOX-mediated cardiomyopathy.anthracyclines; frataxin; cardiomyopathy; iron overload; mitochondrial damage; oxidative stress DOXORUBICIN (DOX) IS ONE OF the most widely used anti-neoplastic agents used for the treatment of a wide range of solid tumors and leukemia in children and adults (10,36,40). Despite its therapeutic usage, the clinical use of DOX is severely limited due to its cumulative dose-dependent cardiotoxicity, which develops over time into congestive heart failure (30). During this process, mitochondrial dysfunction has been observed to be fundamentally involved in the development of heart failure due to the dysregulation of mitochondrial bioenergetics and the generation of intracellular reactive oxygen species (ROS). The mechanism of DOX-induced cardiotoxicity at the cellular and subcellular levels is highly debatable. However, much attention has been attributed to the DOX-mediated formation of mitochondrial ROS. Although the role of iron has not been emphasized in the failing myocardial model, the role of iron in the formation of ROS has gained significance at the clinical setting with the usage of dexrazoxane (DXZ). DXZ, an iron chelator, is known to induce degradation of topo2␤ and prevent the DOX-mediated initiation of the DNA damage signal, H2AX-␥, in H9C2 cardiomyoblasts (28). However, the use of DXZ has been limited due to its interference with antitumor acti...

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“…Neonatal Rat Cardiomyocyte Culture-Cardiomyocytes were isolated from CO 2 -asphyxiated 1-day-old Sprague-Dawley rats using an isolation kit from Worthington, following the manufacturer's instructions (36). Purified cardiomyocytes were plated onto gelatin-coated 12-well plates in high glucose (4.5 g/liter) Dulbecco's modified Eagle's medium supplemented with 10% horse serum, 5% fetal bovine serum, 100 M bromodeoxyuridine, 2 mM glutamine, 100 units/ml penicillin, and 100 g/ml streptomycin and maintained in humidified tissue culture incubators at 37°C and 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Adaptation of Myocardial Substrate Metabolism to a Ketogenic Nutrient Environment

Wentz

d’Avignon

Weber

et al. 2010

Journal of Biological Chemistry

108

112

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Heart muscle is metabolically versatile, converting energy stored in fatty acids, glucose, lactate, amino acids, and ketone bodies. Here, we use mouse models in ketotic nutritional states (24 h of fasting and a very low carbohydrate ketogenic diet) to demonstrate that heart muscle engages a metabolic response that limits ketone body utilization. Pathway reconstruction from microarray data sets, gene expression analysis, protein immunoblotting, and immunohistochemical analysis of myocardial tissue from nutritionally modified mouse models reveal that ketotic states promote transcriptional suppression of the key ketolytic enzyme, succinyl-CoA:3-oxoacid CoA transferase (SCOT; encoded by Oxct1), as well as peroxisome proliferatoractivated receptor ␣-dependent induction of the key ketogenic enzyme HMGCS2. Consistent with reduction of SCOT, NMR profiling demonstrates that maintenance on a ketogenic diet causes a 25% reduction of myocardial 13 C enrichment of glutamate when 13 C-labeled ketone bodies are delivered in vivo or ex vivo, indicating reduced procession of ketones through oxidative metabolism. Accordingly, unmetabolized substrate concentrations are higher within the hearts of ketogenic diet-fed mice challenged with ketones compared with those of chow-fed controls. Furthermore, reduced ketone body oxidation correlates with failure of ketone bodies to inhibit fatty acid oxidation. These results indicate that ketotic nutrient environments engage mechanisms that curtail ketolytic capacity, controlling the utilization of ketone bodies in ketotic states.The mammalian heart must maintain constant levels of ATP to perform its mechanical and electrical functions. A variety of experimental approaches have established that cardiomyopathy is associated with changes in cardiac energy metabolism and that altered energy metabolism can cause cardiomyopathy (1-5). In the normal adult heart, mitochondrial oxidative phosphorylation provides more than 95% of the ATP generated. Substrate utilization is dynamic, and metabolic flexibility under differing physiological conditions is an important adaptive property of myocardium (6 -8). Adaptations over time are

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Comparative toxicity of allylamine and acrolein in cultured myocytes and fibroblasts from neonatal rat heart

Cited by 97 publications

References 17 publications

FGF23 induces left ventricular hypertrophy

FGF23 induces left ventricular hypertrophy

The role of frataxin in doxorubicin-mediated cardiac hypertrophy

Adaptation of Myocardial Substrate Metabolism to a Ketogenic Nutrient Environment

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