Key result
Chronic alcohol exposure in mice induced cardiac oxidative stress, cell death, and remodeling by impairing glyceraldehyde-3-phosphate dehydrogenase and altering glucose metabolism.
Alcohol-induced oxidative stress and impaired glucose metabolism via GAPDH inhibition are causal factors in the development of alcoholic cardiomyopathy, which can be mitigated by antioxidant therapy in preclinical models.
Hypothesis-generating for GAPDH as a target in alcoholic cardiomyopathy; leaves open translation to human therapy.
Heavy consumption of alcohol induces cardiomyopathy and is associated with metabolic changes in the heart. The role of altered metabolism in the development of alcoholic cardiomyopathy remains largely unknown but is examined in the present study. The effect of chronic alcohol consumption on cardiac damage was examined in mice fed an alcohol or isocaloric control diet for 2 months. Signaling pathways of alcohol-induced metabolic alteration and pathologic changes were examined in both animal hearts and H9c2 cell cultures. Compared with controls, the hearts from the alcohol-fed mice exhibited cardiac oxidative stress, cell death, a fibrotic response, hypertrophic remodeling, and the eventual development of cardiac dysfunction. All these detrimental effects could be ameliorated by superoxide dismutase mimic Mn (111) tetrakis 1-methyl 4-pyridylporphyrin pentachloride (MnTMPyP) therapy. A mechanistic study showed that chronic alcohol exposure enhanced the expression of proteins regulating fatty acid uptake but impaired the expression of proteins involved in mitochondrial fatty acid oxidation, which compensatively geared the heart to the suboptimal energy source, glucose. However, chronic alcohol exposure also impaired the glycolytic energy production step regulated by glyceraldehyde-3-phosphate dehydrogenase, which further feeds back to enhance glucose uptake signaling and the accumulation of glycolytic intermediate product fructose, resulting in aggravation of alcohol-induced cardiac oxidative stress, cell death, and remodeling. All these dysmetabolic alterations could be normalized by MnTMPyP treatment, along with significant improvement in cardiac cell death and remodeling. These results demonstrate that alcohol-induced oxidative stress and altered glucose metabolism are causal factors for the development of alcoholic cardiomyopathy.
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Yan et al. (2017) studied Alcoholic cardiomyopathy. Chronic alcohol consumption vs. Isocaloric control diet was evaluated on Cardiac damage (oxidative stress, cell death, fibrotic response, hypertrophic remodeling, cardiac dysfunction) and metabolic alterations. Chronic alcohol exposure in mice induced cardiac oxidative stress, cell death, and remodeling by impairing glyceraldehyde-3-phosphate dehydrogenase and altering glucose metabolism.
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