Cardiac Hypertrophy in Mice with Long-Chain Acyl-CoA Dehydrogenase (LCAD) or Very Long-Chain Acyl-CoA Dehydrogenase (VLCAD) Deficiency

Department of Genetics, University of Alabama at Birmingham, USA.
Laboratory Investigation (Impact Factor: 3.68). 10/2009; 89(12):1348-54. DOI: 10.1038/labinvest.2009.86
Source: PubMed

ABSTRACT Cardiac hypertrophy is a common finding in human patients with inborn errors of long-chain fatty acid oxidation. Mice with either very long-chain acyl-CoA dehydrogenase deficiency (VLCAD−/−) or long-chain acyl-CoA dehydrogenase deficiency (LCAD−/−) develop cardiac hypertrophy. Cardiac hypertrophy, initially measured using heart/body weight ratios, was manifested most severely in LCAD−/− male mice. VLCAD−/− mice, as a group, showed a mild increase in normalized cardiac mass (8.8% hypertrophy compared to all wild-type [WT] mice). In contrast, LCAD−/− mice as a group showed more severe cardiac hypertrophy (32.2% increase compared to all WT mice). Based on a clear male predilection, we investigated the role of dietary plant estrogenic compounds commonly found in mouse diets due to soy or alfalfa components providing natural phytoestrogens or isoflavones in cardioprotection of LCAD−/− mice. Male LCAD−/− mice fed an isoflavone-free test diet had more severe cardiac hypertrophy (58.1% hypertrophy compared to WT mice fed the same diet. There were no significant differences in the female groups fed any of the diets. Echocardiography measurement performed on male LCAD deficient mice fed a standard diet at ~3 months of age confirmed the substantial cardiac hypertrophy in these mice compared with WT controls. Left ventricular wall thickness of interventricular septum and posterior wall was remarkably increased in LCAD−/− mice compared with that of WT controls. Accordingly, the calculated LV mass after normalization to body weight was increased about 40% in the LCAD−/− mice compared with WT mice. In summary, we found that metabolic cardiomyopathy, expressed as hypertrophy, developed in mice due to either VLCAD deficiency or LCAD deficiency; however, LCAD deficiency was the most profound and appeared to be attenuated either by endogenous estrogen in females or phytoestrogens in the diet as isoflavones in males.

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Available from: Stepehn Barnes, Oct 08, 2014
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    • "Inhibition of CPT1 in cardiac tissue has been demonstrated to induce cardiac hypertrophy [33,34]. Similarly, cardiac hypertrophy was found in mice deficient in VLCAD or LCAD [35]. Further evidence for a putative role of PPARα in cardiac hypertrophy comes from studies on fibroblast growth factor 21 (FGF21), which is expressed in and released by cardiomyocytes through a PPARα - dependent mechanism [36]. "
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    ABSTRACT: Background Cardiac pathological hypertrophy is associated with a significantly increased risk of coronary heart disease and has been observed in diabetic patients treated with rosiglitazone whereas most published studies do not suggest a similar increase in risk of cardiovascular events in pioglitazone-treated diabetic subjects. This study sought to understand the pathophysiological and molecular mechanisms underlying the disparate cardiovascular effects of rosiglitazone and pioglitazone and yield knowledge as to the causative nature of rosiglitazone-associated cardiac hypertrophy. Methods We used a high-fat diet-induced pre-diabetic mouse model to allow bioinformatics analysis of the transcriptome of the heart of mice treated with rosiglitazone or pioglitazone. Results Our data show that rosiglitazone and pioglitazone both markedly improved systemic markers for glucose homeostasis, fasting plasma glucose and insulin, and the urinary excretion of albumin. Only rosiglitazone, but not pioglitazone, tended to increase atherosclerosis and induced pathological cardiac hypertrophy, based on a significant increase in heart weight and increased expression of the validated markers, ANP and BNP. Functional enrichment analysis of the rosiglitazone-specific cardiac gene expression suggests that a shift in cardiac energy metabolism, in particular decreased fatty acid oxidation toward increased glucose utilization as indicated by down regulation of relevant PPARα and PGC1α target genes. This underlies the rosiglitazone-associated pathological hypertrophic cardiac phenotype in the current study. Conclusion Application of a systems biology approach uncovered a shift in energy metabolism by rosiglitazone that may impact cardiac pathological hypertrophy.
    BMC Medical Genomics 06/2014; 7(1):35. DOI:10.1186/1755-8794-7-35 · 2.87 Impact Factor
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    • "In particular, the LCAD knockout mouse model accumulates the same acylcarnitine species as occur in VLCADD patients and present with a prominent cardiac hypertrophy at birth [16]. With regard to the heart, VLCAD −/− mice have been reported to display an altered calcium homeostasis [17], prolonged QT interval [18] as well as a mild hypertrophy at three months of age [19] while they are fully asymptomatic at birth although lacking the complete Acadvl gene. These characteristics make VLCAD −/− mice an excellent model for the investigation of pathomechanisms involved in the development of symptoms caused by the lack of VLCAD long-term. "
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    ABSTRACT: Hypertrophic cardiomyopathy is a typical manifestation of very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), the most common long-chain β-oxidation defects in humans; however in some patients cardiac function is fully compensated. Cardiomyopathy may also be reversed by supplementation of medium-chain triglycerides (MCT). We here characterize cardiac function of VLCAD-deficient (VLCAD-/-) mice over one year. Furthermore, we investigate the long-tern effect of a continuous MCT diet on the cardiac phenotype. We assessed cardiac morphology and function in VLCAD-/- mice by in vivo MRI. Cardiac energetics were measured by 31P-MRS and myocardial glucose uptake was quantified by positron-emission-tomography (PET). Metabolic adaptations were identified by the expression of genes regulating glucose and lipid metabolism using real-time-PCR. VLCAD-/- mice showed a progressive decrease in heart function over 12 months accompanied by a reduced phosphocreatine-to-ATP-ratio indicative of chronic energy deficiency. Long-term MCT supplementation aggravated the cardiac phenotype into dilated cardiomyopathy with features similar to diabetic heart disease. Cardiac energy production and function in mice with a β-oxidation defect cannot be maintained with age. Compensatory mechanisms are insufficient to preserve the cardiac energy state over time. However, energy deficiency by impaired β-oxidation and long-term MCT induce cardiomyopathy by different mechanisms. Cardiac MRI and MRS may be excellent tools to assess minor changes in cardiac function and energetics in patients with β-oxidation defects for preventive therapy.
    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 05/2014; 1842(5). DOI:10.1016/j.bbadis.2014.02.001 · 4.88 Impact Factor
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    • "It has been suggested that low RCI in exercise mice might be due to mitochondrial damage. The reason for this has not been fully explained, but a study proposed that cardiac mitochondrial functions may be impaired resulting in significant metabolic effects on lipid metabolism8). The results of that study indicate that care should be taken before assigning overweight adults an exercise program to avoid any side effects from this type of exercise. "
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    ABSTRACT: [Purpose] The purpose of this study was to investigate the effects of 8 weeks of endurance exercise on the cardiac mitochondrial function of mice. [Subjects] Ten 129 SvJ/C57BL6 Male mice were used. The mice were randomly divided into an exercise group (n=5; mean ± SD weight, 27.4 ± 1.6 g) and a control (n=5; mean ± SD weight, 28.2 ± 1.1 g). The exercise mice ran on a motor driven treadmill 5 days per week for 30 minutes at a speed of 24 m/min for 8 weeks. Mitochondrial function as measured RCI was compared between the exercise and control group mice using an independent t test. [Results] The exercise mice had a significantly greater state 4 respiration than to the sedentary control mice. There was also a significant difference in RCI between exercise and sedentary control mice. [Conclusion] Endurance exercise decreased RCI, indicating an uncoupling of respiration and oxidative phosphorylation.
    Journal of Physical Therapy Science 10/2013; 25(10):1317-1319. DOI:10.1589/jpts.25.1317 · 0.39 Impact Factor
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