Acyl-CoA thioesterase 1 (ACOT1) overexpression alleviates heart failure by inhibiting oxidative stress and cardiomyocyte apoptosis through the Kelch-like ECH-associated protein1-NF-E2-related factor2 (KEAP1-NRF2) pathway.

Abstract

Heart failure (HF) is a clinical syndrome related to multiple causes, including oxidative stress. Acyl-CoA thioesterase 1 (ACOT1) is an enzyme in fatty acids metabolism, but it remains unclear in HF. Transverse aortic coarctation induced HF mouse model and hypoxia-stimulated cardiomyocyte (HL-1) model were established. ACOT1 expression was down-regulated in heart tissues of HF mice. Adeno-associated virus serotype 9 (AAV9)-mediated ACOT1 overexpression improved cardiac function and pathological injury of heart tissues in transverse aortic coarctation (TAC)-induced HF mice. ACOT1 overexpression ameliorated oxidative stress in heart tissues of HF mice and hypoxia-stimulated HL-1 cells, as indicated by reduced reactive oxygen species (ROS) and malondialdehyde (MDA) levels and elevated superoxide dismutase (SOD) and glutathione (GSH) levels. We found that ACOT1 overexpression inhibited apoptosis both in vivo and in vitro, with decreased protein levels of cleaved PARP, cleaved CASPASE-3, and cleaved CASPASE-9. Mechanically, ACOT1 activated Kelch-like ECH-associated protein1-NF-E2-related factor2 (KEAP1-NRF2) pathway, leading to the nuclear translocation of NRF2 and increased NRF2-regulated gene Nqo1 expression. Rescue experiment indicated that ML385 (NRF2 inhibitor) abolished the effect of ACOT1 overexpression on oxidative stress. Collectively, these results suggested that ACOT1 overexpression protects heart from injury by inhibiting oxidative stress and apoptosis, possibly through activating KEAP1-NRF2 pathway.