Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evidence is emerging that systemic metabolic disturbances contribute to cardiac myocyte dysfunction and clinically apparent heart failure, independent of associated coronary artery disease. To test the hypothesis that perturbation of lipid homeostasis in cardiomyocytes contributes to cardiac dysfunction, we engineered transgenic mice with cardiac-specific overexpression of fatty acid transport protein 1 (FATP1) using the alpha-myosin heavy chain gene promoter. Two independent transgenic lines demonstrate 4-fold increased myocardial free fatty acid (FFA) uptake that is consistent with the known function of FATP1. Increased FFA uptake in this model likely contributes to early cardiomyocyte FFA accumulation (2-fold increased) and subsequent increased cardiac FFA metabolism (2-fold). By 3 months of age, transgenic mice have echocardiographic evidence of impaired left ventricular filling and biatrial enlargement, but preserved systolic function. Doppler tissue imaging and hemodynamic studies confirm that these mice have predominantly diastolic dysfunction. Furthermore, ambulatory ECG monitoring reveals prolonged QT(c) intervals, reflecting reductions in the densities of repolarizing, voltage-gated K+ currents in ventricular myocytes. Our results show that in the absence of systemic metabolic disturbances, such as diabetes or hyperlipidemia, perturbation of cardiomyocyte lipid homeostasis leads to cardiac dysfunction with pathophysiological findings similar to those in diabetic cardiomyopathy. Moreover, the MHC-FATP model supports a role for FATPs in FFA import into the heart in vivo.
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PMID:Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy. 1561 39

Alterations in cardiac glucose and fatty acid metabolism are possible contributors to the pathogenesis of heart failure in obesity. Here we examined the effect of leptin, the product of the obese (ob) gene, on metabolism in murine cardiomyocytes. Neither short-term (1 hour) nor long-term (24 hours) treatment with leptin (60 nmol/L) altered basal or insulin-stimulated glucose uptake and oxidation, glycogen synthesis, insulin receptor substrate 1 tyrosine, Akt, or glycogen synthase kinase 3beta phosphorylation. Extracellular lactate levels were also unaffected by leptin. However, leptin increased basal and insulin-stimulated palmitate uptake at both short and long exposure times and this corresponded with increased cell surface CD36 levels and elevated fatty acid transport protein 1 (FATP1) and CD36 protein content. Whereas short-term leptin treatment increased fatty acid oxidation, there was a decrease in oxidation after 24 hours. The former corresponded with increased acetyl coenzyme A carboxylase phosphorylation and the latter with increased expression of this enzyme. The discrepancy between uptake and oxidation of fatty acids led to a transient decrease in intracellular lipid content with lipid accumulation ensuing after 24 hours. In summary, we demonstrate that leptin did not alter glucose uptake or metabolism in murine cardiomyocytes. However, fatty acid uptake increased while oxidation decreased over time leading to intracellular lipid accumulation, which may lead to lipotoxic damage in heart failure.
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PMID:Distinct effects of short- and long-term leptin treatment on glucose and fatty acid uptake and metabolism in HL-1 cardiomyocytes. 1683 43