Letrozole Accelerates Metabolic Remodeling through Activation of Glycolysis in Cardiomyocytes: A Role beyond Hormone Regulation.
Jun H HeoSang R LeeSeong Lae JoHyun YangHye-Won LeeIn-Jeoung BaekPublished in: International journal of molecular sciences (2022)
Estrogen receptor-positive (ER+) breast cancer patients are recommended hormone therapy as a primary adjuvant treatment after surgery. Aromatase inhibitors (AIs) are widely administered to ER+ breast cancer patients as estrogen blockers; however, their safety remains controversial. The use of letrozole, an AI, has been reported to cause adverse cardiovascular effects. We aimed to elucidate the effects of letrozole on the cardiovascular system. Female rats exposed to letrozole for four weeks showed metabolic changes, i.e., decreased fatty acid oxidation, increased glycolysis, and hypertrophy in the left ventricle. Although lipid oxidation yields more ATP than carbohydrate metabolism, the latter predominates in the heart under pathological conditions. Reduced lipid metabolism is attributed to reduced β-oxidation due to low circulating estrogen levels. In letrozole-treated rats, glycolysis levels were found to be increased in the heart. Furthermore, the levels of glycolytic enzymes were increased (in a high glucose medium) and the glycolytic rate was increased in vitro (H9c2 cells); the same was not true in the case of estrogen treatment. Reduced lipid metabolism and increased glycolysis can lower energy supply to the heart, resulting in predisposition to heart failure. These data suggest that a letrozole-induced cardiac metabolic remodeling, i.e., a shift from β-oxidation to glycolysis, may induce cardiac structural remodeling.
Keyphrases
- estrogen receptor
- high glucose
- polycystic ovary syndrome
- heart failure
- early breast cancer
- fatty acid
- hydrogen peroxide
- endothelial cells
- left ventricular
- atrial fibrillation
- induced apoptosis
- mitral valve
- bone marrow
- combination therapy
- machine learning
- electronic health record
- big data
- oxidative stress
- breast cancer cells
- drug induced
- cardiac resynchronization therapy