3,3′,5-triiodothyroxine inhibits apoptosis and oxidative stress by the PKM2/PKM1 ratio during oxygen-glucose deprivation/reperfusion AC16 and HCM-a cells

Oxidative stress (OS) plays a crucial role in the development of myocardial disease, which can induce the dysfunction of cardiac muscle cells. 3,3′,5-triiodothyroxine (T3) is a hormone secreted from the thyroid gland that has been shown to protect cells by improving the redox state and to regulate the expression of pyruvate kinase muscle isozyme (PKM, including two isoforms PKM1 and PKM2). The present study aimed to reveal the key effects of T3 on protecting human myocardial cell lines from oxidative stress and the downstream molecular mechanism. An oxygen-glucose deprivation/reperfusion model (OGDR) and three subtypes of the deiodinase family (DIO1, DIO2, and DIO3), which convert thyroxine (T4) to T3, were tested in this model. Our results show that the expression of DIO1, DIO2 and T3 was downregulated, but DIO3 was upregulated in OGDR-treated AC16 and HCM-a cells. Then, OGDR-treated cells were treated with T3 and T4. The results show that T3 inhibited the expression of reactive oxygen species (ROS) and malonic dialdehyde (MDA), but upregulated glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD). The effects of T4 were not notable. T3 also protected OGDR cells from apoptosis and upregulated the PKM2/PKM1 ratio. Further mechanistic studies found that PKM2 inhibition by small interfering RNA (siRNA) could attenuate the anti-OS and anti-apoptotic effects of T3. These findings suggest that T3 can inhibit apoptosis and oxidative stress in OGDR-treated AC16 and HCM-a cells by regulating the PKM2/PKM1 ratio.