Premature Death of Sleep Fragmented Males is Associated With An Accumulation of Reactive Oxygen Species In The Gut

Abstract

Abstract 70 million Americans report insufficient sleep due to work or lifestyle choices. Decreased duration and poor sleep quality are associated with high rates of CVD and is strongly associated with increased risk of all-cause mortality. The effects of gender have been studied in CVD, but the impact of sexual dimorphism in Sleep Fragmented (SF)-associated atherogenesis is not known. Recently, we found that high fat diet (HFD) fed male Apoe −/−mice on SF experienced premature death. 80% of males did not survive past week 2 of SF, while 80% of females survived past week 8 under same conditions. We sought to identify a cause of premature death in HFD fed male Apoe −/−mice following sleep fragmentation. Interestingly, HFD fed male Ldlr −/−mouse did not experience premature death when SF, suggesting that ApoE absence, not hyperlipidemia, plays an essential function in the induction of death. Furthermore, oral 17β-Estradiol was able to rescue HFD fed male Apoe −/−mice from SF induced premature death. Compared to controls, SF, HFD fed male Apoe −/−mice had decreased body weight and increased circulating LPS, ROS and cell-free dsDNA at death. Finally, the small intestines SF, HFD fed male Apoe −/−mice had increased ROS and decreased tight junction protein (Tjp1) expression, suggesting compromised intestinal barrier function. Our data suggests that a combination of known risk factors for CVD (male sex, ApoE genotype, and HFD) results in premature death when combined with inadequate sleep. Furthermore, our data suggests that this specific combination of co-factors might result in premature death due to a systemic increase in oxidative stress, possibly caused by leakage of LPS from the gut, which may be alleviated through the administration of 17β-Estradiol. Supported by project–initiation funds from the Center for Integrative Neuroscience and Inflammatory Diseases and AHA Predoctoral (20PRE35180156)