Succinate level is increased and succinate dehydrogenase exerts forward and reverse catalytic activities in lipopolysaccharides-stimulated cardiac tissue: The protective role of dimethyl malonate

This study aimed to investigate the alterations of myocardial succinate and fumarate levels with or without succinate dehydrogenase (SDH) inhibitor dimethyl malonate during 24 h of lipopolysaccharides (LPS) challenge, as well as the effects of dimethyl malonate on the impaired cardiac tissue. Myocardial succinate and fumarate levels were increased in the initial 9 h of LPS challenge. During this time, dimethyl malonate increased the succinate level, decreased the fumarate level, aggravated the cardiac dysfunction, reduced the oxidative stress, had little effect on interleukin-1 beta production, promoted interleukin-10 production and bothered the ATP pro-duction. Co-treatment with exogenous succinate significantly increased interleukin-1 beta production in this period. After 12 h of LPS challenge, myocardial the succinate level increased sharply, while the fumarate level gradually decreased. During 12-24 h of LPS challenge, dimethyl malonate effectively reduced the succinate level, increased the fumarate level, improved cardiac dysfunction, inhibited interleukin-1 beta production, and had little effect on oxidative stress, interleukin-10 production, and ATP production. LPS challenge also significantly increased the myocardial succinate receptor 1 expression and circulating succinate level. Inhibition of succinate receptor 1 significantly reduced the mRNA expression of interleukin-1 beta. In conclusion, the current study suggests that myocardial succinate accumulates during LPS challenge, and that SDH activity may be transformed (from for-ward to reversed) and involved in a line of stress response. Dimethyl malonate inhibits SDH and, depending on the time of treatment, reduces LPS-induced cardiac impairment. Furthermore, accumulated succinate exerts pro-inflammatory effects partly via succinate receptor 1 signaling.