Sepsis-associated cardiac injury represents a significant complication of critical infections, leading to cardiac dysfunction, myocardial oedema and myocardial inflammation. These manifestations result in severe target organ damage with an unfavourable prognosis and an elevated risk of mortality. The clearance of inflammatory immune cells infiltrating the heart and the attenuation of myocardial oedema are key functions of the cardiac lymphatic system. This study investigates the protective effects of 4-OI (4-octyl itaconate) against LPS-mediated cardiac injury in a mouse model. We established acute cardiac dysfunction through intraperitoneal LPS injection and assessed cardiac function via small-animal ultrasound. Results indicated that LPS significantly impaired cardiac function, evidenced by decreased left ventricular ejection fraction (EF%) and fractional shortening (FS%). Treatment with 4-OI improved these parameters and reduced serum markers of myocardial injury, including cTnT and LDH. Additionally, 4-OI mitigated LPS-induced cardiac edema and vascular leakage, as demonstrated by Evans Blue dye assays. Histological analyses revealed that 4-OI reduced inflammatory cell infiltration, particularly M1-type macrophages, and stabilized cardiac lymphatic endothelial function. To further elucidate the mechanism, we blocked lymphatic reflux via thoracic duct ligation, which diminished the therapeutic efficacy of 4-OI, indicating the involvement of cardiac lymphatics in its protective effects. Furthermore, in vitro studies showed that 4-OI reduced inflammatory responses in lymphatic endothelial cells (LECs) and stabilized intercellular junctions disrupted by LPS. Network pharmacological analysis identified RhoA/ROCK1 signaling as a potential target of 4-OI in treating LPS-induced endothelial dysfunction. In conclusion, 4-OI exhibits significant cardioprotective effects against LPS-induced acute cardiac dysfunction, primarily through modulation of inflammatory responses and stabilization of lymphatic endothelial function.
Wu et al. (Mon,) studied this question.