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Publications (2)9.82 Total impact

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    ABSTRACT: The renin-angiotensin system (RAS) may alter cardiac energy metabolism in heart failure. Angiotensin II (Ang II), the main effector of the RAS in heart failure, has emerged as an important regulator of cardiac hypertrophy and energy metabolism. We studied the metabolic perturbations and insulin response in an Ang II-induced hypertrophy model. Ex vivo heart perfusion showed that hearts from Ang II-treated mice had a lower response to insulin with significantly reduced rates of glucose oxidation in association with increased pyruvate dehydrogenase kinase 4 (PDK4) levels. Palmitate oxidation rates were significantly reduced in response to insulin in vehicle-treated hearts but remained unaltered in Ang II-treated hearts. Furthermore, phosphorylation of Akt was also less response to insulin in Ang II-treated WT mice, suggestive of insulin resistance. We evaluated the role of PDK4 in the Ang II-induced pathology and showed that deletion of PDK4 prevented Ang II-induced diastolic dysfunction and normalized glucose oxidation to basal levels. Ang II-induced reduction in the levels of the deacetylase, SIRT3, was associated with increased acetylation of PDH and a reduced PDH activity. In conclusion, our findings show that a combination of insulin resistance and decrease in PDH activity are involved in Ang II-induced reduction in glucose oxidation, resulting in cardiac inefficiency. Ang II reduces PDH activity via acetylation of PDH complex, as well as increased phosphorylation in response to increased PDK4 levels.
    AJP Heart and Circulatory Physiology 02/2013; · 4.01 Impact Factor
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    ABSTRACT: During reperfusion of the ischaemic myocardium, fatty acid oxidation rates quickly recover, while glucose oxidation rates remain depressed. Direct stimulation of glucose oxidation via activation of pyruvate dehydrogenase (PDH), or secondary to an inhibition of malonyl CoA decarboxylase (MCD), improves cardiac functional recovery during reperfusion following ischaemia. However, the effects of such interventions on the evolution of myocardial infarction are unknown. The purpose of this study was to determine whether infarct size is decreased in response to increased glucose oxidation. In vivo, direct stimulation of PDH in mice with the PDH kinase (PDHK) inhibitor, dichloroacetate, significantly decreased infarct size following temporary ligation of the left anterior descending coronary artery. These results were recapitulated in PDHK 4-deficient (PDHK4-/-) mice, which have enhanced myocardial PDH activity. These interventions also protected against ischaemia/reperfusion injury in the working heart, and dichloroacetate failed to protect in PDHK4-/- mice. In addition, there was a dramatic reduction in the infarct size in malonyl CoA decarboxylase-deficient (MCD-/-) mice, in which glucose oxidation rates are enhanced (secondary to an inhibition of fatty acid oxidation) relative to their wild-type littermates (10.8 ± 3.8 vs. 39.5 ± 4.7%). This cardioprotective effect in MCD-/- mice was associated with increased PDH activity in the ischaemic area at risk (1.89 ± 0.18 vs. 1.52 ± 0.05 μmol/g wet weight/min). These findings demonstrate that stimulating glucose oxidation via targeting either PDH or MCD decreases the infarct size, validating the concept that optimizing myocardial metabolism is a novel therapy for ischaemic heart disease.
    Cardiovascular Research 03/2012; 94(2):359-69. · 5.81 Impact Factor