Chitoheptaose Promotes Heart Rehabilitation in a Rat Myocarditis Model by Improving Antioxidant, Anti-Inflammatory, and Antiapoptotic Properties

Abstract

Background. Myocarditis is one of the important causes of dilated cardiomyopathy, cardiac morbidity, and mortality worldwide. Chitosan oligosaccharides (COS) may have anti-inflammatory and cardioprotective effects on myocarditis. However, the exact molecular mechanism for the effects of functional COS on myocarditis remains unclear. Methods. Anti-inflammatory activities of COS (chitobiose, chitotriose, chitotetraose, chitopentaose, chitohexaose, chitoheptaose, and chitooctaose) were measured in lipopolysaccharide- (LPS-) stimulated RAW264.7 cells. A rat model with myocarditis was established and treated with chitopentaose, chitohexaose, chitoheptaose, and chitooctaose. Serum COS were measured by using high-performance liquid chromatography (HPLC) in all rats. Myocarditis injury, the levels of reactive oxygen species (ROS), reactive nitrogen species (RNS), inflammatory factors, and apoptotic factors were also measured. Pearson’s correlation coefficient test was used to explore the relationship between the levels of ROS/RNS and cardiac parameters. Results. Among all chitosan oligosaccharides, the $\text{COS}>\text{degrees}\text{of}\text{polymerization}\left(\text{DP}\right)4$ showed anti-inflammatory activities (the activity order was chitopentaose<chitohexaose<chitoheptaose<chitooctaose) by reducing the levels of interleukin- (IL-) 1 β, IL-17A, and interferon- (IFN-) γ and increasing the level of IL-10. However, the serum level of chitooctaose was low whereas it showed significant therapeutic effects on myocarditis by improving cardiac parameters (left ventricular internal dimension, both end-systolic and end-diastolic, ejection fraction, and fractional shortening), inflammatory cytokines (IL-1 β, IL-10, IL-17A, and IFN- γ), oxidative factors (ROS and RNS), and apoptotic factors (caspase 3, BAX, and BCL-2) when compared with chitopentaose, chitohexaose, and chitooctaose ( $\text{COS}\text{DP}>4$). The levels of ROS/RNS had a strong relationship with cardiac parameters. Conclusions. Chitoheptaose plays a myriad of cardioprotective roles in the myocarditis model via its antioxidant, anti-inflammatory, and antiapoptotic activities.