Takao Kato1, Shinichiro Niizuma1, Yasutaka Inuzuka1, Tsuneaki Kawashima1, Jun Okuda1, Yodo Tamaki1, Yoshitaka Iwanaga1, Michiko Narazaki1, Tetsuya Matsuda1, Tomoyoshi Soga1, Toru Kita1, Takeshi Kimura1
1From the Department of Cardiovascular Medicine (T. Kato, S.N., Y.I., T. Kawashima, J.O., Y.T., Y.I., T. Kita, T. Kimura, T.S.), Graduate School of Medicine, and Department of Systems Science (M.N., T.M.), Graduate School of Informatics, Kyoto University, Kyoto, and Institute for Advanced Bioscience (T.S.), Keio University, Yamagata, Japan.
Tóm tắt
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.
