Beta-Hydroxybutyrate, A Ketone Body, Potentiates The Antioxidant Defense Via Thioredoxin 1 Upregulation In Cardiomyocytes

Thioredoxin 1 (Trx1) is a major antioxidant that acts adaptively to protect the heart during the development of diabetic cardiomyopathy. The molecular mechanism(s) responsible for regulating the Trx1 level and/or activity during diabetic cardiomyopathy is unknown. beta-hydroxybutyrate (beta HB), a major ketone body in mammals, acts as an alternative energy source in cardiomyocytes under stress, but it also appears to be involved in additional mechanisms that protect the heart against stress. beta HB upregulated Trx1 in primary cultured cardiomyocytes in a dose- and a time-dependent manner and a ketogenic diet upregulated Trx1 in the heart. beta HB protected cardiomyocytes against H2O2-induced death, an effect that was abolished in the presence of Trx1 knockdown. beta HB also alleviated the H2O2-induced inhibition of mTOR and AMPK, known targets of Trx1, in a Trx1-dependent manner, suggesting that beta HB potentiates Trx1 function. It has been shown that beta HB is a natural inhibitor of HDAC1 and knockdown of HDAC1 upregulated Trx1 in cardiomyocytes, suggesting that beta HB may upregulate Trx1 through HDAC inhibition. beta HB induced Trx1 acetylation and inhibited Trx1 degradation, suggesting that beta HB-induced inhibition of HDAC1 may stabilize Trx1 through protein acetylation. These results suggest that beta HB potentiates the antioxidant defense in cardiomyocytes through the inhibition of HDAC1 and the increased acetylation and consequent stabilization of Trx1. Thus, modest upregulation of ketone bodies in diabetic hearts may protect the heart through the upregulation of Trx1.