Ashwin Akki1, Anne-Marie L Seymour. 1. Department of Biological Sciences, Hull York Medical School, University of Hull, Cottingham Road, Kingston-upon-Hull HU6 7RX, UK.
Abstract
AIMS: Metabolic remodelling in cardiac hypertrophy is underscored by a reduction in fatty acid (FA) oxidation. We tested whether this decline in FA oxidation in the presence of enhanced FA supply may predispose the hypertrophied myocardium to lipid accumulation, functional deterioration, and eventually heart failure. METHODS: and results Left ventricular hypertrophy was induced surgically in Sprague-Dawley rats by inter-renal aortic constriction. Rats were fed a Western diet (WD, 45% kcal from lipids) or standard diet (SD, 12% kcal from fat) for 9 weeks post-surgery. Hearts were perfused in the isovolumic mode with a physiological mixture of substrates including 5 mM 1-(13)C glucose, 1 mM 3-(13)C lactate, and 0.3 mM U-(13)C palmitate, and cardiac function was monitored. Real-time PCR was used to determine transcript levels of peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARalpha-regulated metabolic enzymes. Palmitate oxidation and PPARalpha-regulated gene expression were markedly reduced in the hypertrophied myocardium of rats fed SD. However, 9 weeks of WD normalized both palmitate oxidation and PPARalpha-regulated gene expression but significantly increased glucose and lactate oxidation in the hypertrophied hearts. This was accompanied by cardiac triglyceride accumulation and a decline in ventricular function despite an increase in oxygen consumption. CONCLUSION: These results highlight that WD-induced dysregulation of FA metabolism has deleterious functional consequences in cardiac hypertrophy.
AIMS: Metabolic remodelling in cardiac hypertrophy is underscored by a reduction in fatty acid (FA) oxidation. We tested whether this decline in FA oxidation in the presence of enhanced FA supply may predispose the hypertrophied myocardium to lipid accumulation, functional deterioration, and eventually heart failure. METHODS: and results Left ventricular hypertrophy was induced surgically in Sprague-Dawley rats by inter-renal aortic constriction. Rats were fed a Western diet (WD, 45% kcal from lipids) or standard diet (SD, 12% kcal from fat) for 9 weeks post-surgery. Hearts were perfused in the isovolumic mode with a physiological mixture of substrates including 5 mM 1-(13)C glucose, 1 mM 3-(13)C lactate, and 0.3 mM U-(13)C palmitate, and cardiac function was monitored. Real-time PCR was used to determine transcript levels of peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARalpha-regulated metabolic enzymes. Palmitate oxidation and PPARalpha-regulated gene expression were markedly reduced in the hypertrophied myocardium of rats fed SD. However, 9 weeks of WD normalized both palmitate oxidation and PPARalpha-regulated gene expression but significantly increased glucose and lactate oxidation in the hypertrophied hearts. This was accompanied by cardiac triglyceride accumulation and a decline in ventricular function despite an increase in oxygen consumption. CONCLUSION: These results highlight that WD-induced dysregulation of FA metabolism has deleterious functional consequences in cardiac hypertrophy.
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