Stimulus specific changes of energy metabolism in hypertrophied heart

During the neonatal period, cardiac energy metabolism progresses from a fetal glycolytic profile towards one more dependent on mitochondrial oxidative metabolism. In this study, we identified the effects of cardiac hypertrophy on neonatal cardiac metabolic maturation and its impact on neonatal postischemic functional recovery. Seven-day-old rabbits were subjected to either a sham or a surgical procedure to induce a left-to-right shunt via an aortocaval fistula to cause RV volume-overload. At 3 wk of age, hearts were isolated from both groups and perfused as isolated, biventricular preparations to assess cardiac energy metabolism. Volume-overload resulted in cardiac hypertrophy (16% increase in cardiac mass, P < 0.05) without evidence of cardiac dysfunction in vivo or in vitro. Fatty acid oxidation rates were 60% lower ( P < 0.05) in hypertrophied hearts than controls, whereas glycolysis increased 246% ( P < 0.05). In contrast, glucose and lactate oxidation rates were unchanged. Overall ATP production rates were significantly lower in hypertrophied hearts, resulting in increased AMP-to-ATP ratios in both aerobic hearts and ischemia-reperfused hearts. The lowered energy generation of hypertrophied hearts depressed functional recovery from ischemia. Decreased fatty acid oxidation rates were accompanied by increased malonyl-CoA levels due to decreased malonyl-CoA decarboxylase activity/expression. Increased glycolysis in hypertrophied hearts was accompanied by a significant increase in hypoxia-inducible factor-1α expression, a key transcriptional regulator of glycolysis. Cardiac hypertrophy in the neonatal heart results in a reemergence of the fetal metabolic profile, which compromises ATP production in the rapidly maturing heart and impairs recovery of function following ischemia.

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“…PPAR␣ regulates MCD transcription (22,23,36). We demonstrate that, with PPAR␣ level changes, LV MCD expression increases with age.…”

Section: Discussionmentioning

confidence: 70%

Cardiac hypertrophy in the newborn delays the maturation of fatty acid β-oxidation and compromises postischemic functional recovery

Oka

Lam

Zhang

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…FGF23 and FGF2 treatment also decreased expression of medium chain acyl-CoA dehydrogenase (MCAD), an enzyme that regulates fatty acid oxidation. Cardiomyocytes that undergo hypertrophy shift their primary energy source from fatty acids to carbohydrates (45), which is marked by reduced expression of MCAD (46). Collectively, these data demonstrate that FGF23 exerts direct hypertrophic effects on isolated NRVMs.…”

Section: Figurementioning

confidence: 72%

FGF23 induces left ventricular hypertrophy

Faul¹,

Amaral²,

Oskouei³

et al. 2011

J. Clin. Invest.

1,767

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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“…Studies primarily concerned the FA oxidation pathway and presented the downregulation of genes involved in FA transport and oxidation in pathological hypertrophy, whereas upregulation of several of these genes was observed in adaptive hypertrophy (63). The decreased expression of genes involved in FA oxidation that is observed in pathological hypertrophy is believed to be due to a decline in the activity of peroxisome proliferatoractivated receptor-␣ (PPAR␣), the transcription factor that plays a crucial role in the transcriptional regulation of genes involved in FA metabolism (21,30,52,69). Moreover, expression of PPAR␣ and its downstream targets, i.e., medium-chain acyl-CoA dehydrogenase and carnitine palmitoyltransferase I (CPT I), was upregulated after endurance training (52).…”

mentioning

confidence: 99%

“…The adaptations include increases in cardiac mass and dimension, maximum oxygen consumption, and coronary blood flow (35). Additionally, exercise results in a balanced growth of cardiomyocytes with a normal myofibril to mitochondrial ratio (52,71). Conversely, the hypertrophy observed in different pathological settings is accompanied by cardiac dysfunction or increased morbidity (61).…”

mentioning

confidence: 99%

Expression of lipogenic genes is upregulated in the heart with exercise training-induced but not pressure overload-induced left ventricular hypertrophy

Dobrzyń

Pyrkowska

Duda

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Dobrzyn P, Pyrkowska A, Duda MK, Bednarski T, Maczewski M, Langfort J, Dobrzyn A. Expression of lipogenic genes is upregulated in the heart with exercise training-induced but not pressure overload-induced left ventricular hypertrophy. Am J Physiol Endocrinol Metab 304: E1348 -E1358, 2013. First published April 30, 2013 doi:10.1152/ajpendo.00603.2012.-Cardiac hypertrophy is accompanied by molecular remodeling that affects different cellular pathways, including fatty acid (FA) utilization. In the present study, we show that cardiac lipid metabolism is differentially regulated in response to physiological (endurance training) and pathological [abdominal aortic banding (AAB)] hypertrophic stimuli. Physiological hypertrophy was accompanied by an increased expression of lipogenic genes and the activation of sterol regulatory element-binding protein-1c and Akt signaling. Additionally, FA oxidation pathways regulated by AMPactivated protein kinase (AMPK) and peroxisome proliferator activated receptor-␣ (PPAR␣) were induced in trained hearts. Cardiac lipid content was not changed by physiological stimulation, underlining balanced lipid utilization in the trained heart. Moreover, pathological hypertrophy induced the AMPK-regulated oxidative pathway, whereas PPAR␣ and expression of its downstream targets, i.e., acylCoA oxidase and carnitine palmitoyltransferase I, were not affected by AAB. In contrast, pathological hypertrophy leads to cardiac triglyceride (TG) and diacylglycerol (DAG) accumulation, although the expression of lipogenic genes and the levels of FA transport proteins (CD36 and FATP) were not changed or reduced compared with the sham group. A possible explanation for this phenomenon is a decrease in lipolysis, as evidenced by the increased content of adipose triglyceride lipase inhibitor G0S2, the increased phosphorylation of hormone-sensitive lipase at Ser 565 , and the decreased protein levels of DAG lipase that attenuate TG and DAG contents. The increased TG and DAG accumulation observed in AAB-induced hypertrophy might have lipotoxic effects, thereby predisposing to cardiomyopathy and heart failure in the future. lipogenesis; endurance training; sterol regulatory element-binding protein-1; adipose triglyceride lipase; hormone-sensitive lipase CARDIAC HYPERTROPHY IS ASSOCIATED with extensive remodeling, which in due course will affect cardiac function and ultimately contribute to the transition from compensatory hypertrophy to cardiac failure (70). Molecular remodeling in the heart caused by hypertrophy differs between physiological and pathological stimuli. The physiological cardiac hypertrophy caused by endurance training shows enhancement of cardiac function at rest and during exercise and is not a risk factor for heart failure (19, 29). The adaptations include increases in cardiac mass and dimension, maximum oxygen consumption, and coronary blood flow (35). Additionally, exercise results in a balanced growth of cardiomyocytes with a normal myofibril to mitochondrial ratio (52, 71). Conversely, the hype...

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Stimulus specific changes of energy metabolism in hypertrophied heart

Cited by 46 publications

References 43 publications

Cardiac hypertrophy in the newborn delays the maturation of fatty acid β-oxidation and compromises postischemic functional recovery

Cardiac hypertrophy in the newborn delays the maturation of fatty acid β-oxidation and compromises postischemic functional recovery

FGF23 induces left ventricular hypertrophy

Expression of lipogenic genes is upregulated in the heart with exercise training-induced but not pressure overload-induced left ventricular hypertrophy

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