BACKGROUND: Congestive heart failure (CHF) is associated with a change in cardiac energy metabolism. However, the mechanism by which this change is induced and causes the progression of CHF is unclear. METHODS AND RESULTS: We analyzed the cardiac energy metabolism of Dahl salt-sensitive rats fed a high-salt diet, which showed a distinct transition from compensated left ventricular hypertrophy to CHF. Glucose uptake increased at the left ventricular hypertrophy stage, and glucose uptake further increased and fatty acid uptake decreased at the CHF stage. The gene expression related to glycolysis, fatty acid oxidation, and mitochondrial function was preserved at the left ventricular hypertrophy stage but decreased at the CHF stage and was associated with decreases in levels of transcriptional regulators. In a comprehensive metabolome analysis, the pentose phosphate pathway that regulates the cellular redox state was found to be activated at the CHF stage. Dichloroacetate (DCA), a compound known to enhance glucose oxidation, increased energy reserves and glucose uptake. DCA improved cardiac function and the survival of the animals. DCA activated the pentose phosphate pathway in the rat heart. DCA activated the pentose phosphate pathway, decreased oxidative stress, and prevented cell death of cultured cardiomyocytes. CONCLUSIONS: Left ventricular hypertrophy or CHF is associated with a distinct change in the metabolic profile of the heart. DCA attenuated the transition associated with increased energy reserves, activation of the pentose phosphate pathway, and reduced oxidative stress.
BACKGROUND:Congestive heart failure (CHF) is associated with a change in cardiac energy metabolism. However, the mechanism by which this change is induced and causes the progression of CHF is unclear. METHODS AND RESULTS: We analyzed the cardiac energy metabolism of Dahl salt-sensitive rats fed a high-salt diet, which showed a distinct transition from compensated left ventricular hypertrophy to CHF. Glucose uptake increased at the left ventricular hypertrophy stage, and glucose uptake further increased and fatty acid uptake decreased at the CHF stage. The gene expression related to glycolysis, fatty acid oxidation, and mitochondrial function was preserved at the left ventricular hypertrophy stage but decreased at the CHF stage and was associated with decreases in levels of transcriptional regulators. In a comprehensive metabolome analysis, the pentose phosphate pathway that regulates the cellular redox state was found to be activated at the CHF stage. Dichloroacetate (DCA), a compound known to enhance glucose oxidation, increased energy reserves and glucose uptake. DCA improved cardiac function and the survival of the animals. DCA activated the pentose phosphate pathway in the rat heart. DCA activated the pentose phosphate pathway, decreased oxidative stress, and prevented cell death of cultured cardiomyocytes. CONCLUSIONS:Left ventricular hypertrophy or CHF is associated with a distinct change in the metabolic profile of the heart. DCA attenuated the transition associated with increased energy reserves, activation of the pentose phosphate pathway, and reduced oxidative stress.
Authors: Haipeng Sun; Kristine C Olson; Chen Gao; Domenick A Prosdocimo; Meiyi Zhou; Zhihua Wang; Darwin Jeyaraj; Ji-Youn Youn; Shuxun Ren; Yunxia Liu; Christoph D Rau; Svati Shah; Olga Ilkayeva; Wen-Jun Gui; Noelle S William; R Max Wynn; Christopher B Newgard; Hua Cai; Xinshu Xiao; David T Chuang; Paul Christian Schulze; Christopher Lynch; Mukesh K Jain; Yibin Wang Journal: Circulation Date: 2016-04-08 Impact factor: 29.690
Authors: Brian E Sansbury; Angelica M DeMartino; Zhengzhi Xie; Alan C Brooks; Robert E Brainard; Lewis J Watson; Andrew P DeFilippis; Timothy D Cummins; Matthew A Harbeson; Kenneth R Brittian; Sumanth D Prabhu; Aruni Bhatnagar; Steven P Jones; Bradford G Hill Journal: Circ Heart Fail Date: 2014-04-24 Impact factor: 8.790