Yangxin Tongluo Decoction Protects Against Sepsis-Associated Cardiac Dysfunction Through Regulating Nrf2 Pathway

Sepsis-induced cardiac dysfunction is a major cause of high mortality in critically ill patients. Yangxin Tongluo decoction (YXTLD), a traditional Chinese medicine (TCM) formula, is clinically used for such conditions, but its therapeutic effects and underlying mechanisms remain unclear. This study investigated the protective role of YXTLD against sepsis-associated cardiac dysfunction and its relationship with the Nrf2 signaling pathway.

An in vivo model of sepsis was established in male C57BL/6 mice via intraperitoneal lipopolysaccharide (LPS) injection. Cardiac function was assessed by echocardiography and serum biomarkers (creatine kinase [CK], lactate dehydrogenase [LDH]). In vitro, LPS-stimulated H9c2 cardiomyocytes were treated with various doses of YXTLD. Cell viability, inflammation (interleukin [IL]-1β, IL-6, TNF-α), oxidative stress (reactive oxygen species [ROS], malondialdehyde [MDA], catalase [CAT], glutathione [GSH]), and apoptosis were evaluated. The involvement of the Nrf2 pathway was examined using western blotting. In vivo dosage: YXTLD was administered intraperitoneally five times prior to LPS induction and continued after induction (total of seven doses over 48 h). In vitro concentrations: low (50 μg/mL), medium (100 μg/mL), and high (150 μg/mL) YXTLD.

YXTLD significantly improved cardiac function and alleviated myocardial injury in septic mice, as evidenced by increased ejection fraction (EF; 97.87% ± 1.20% vs. 79.05% ± 3.04%) and fractional shortening (FS; 74.99% ± 5.58% vs. 41.98% ± 2.72%), together with reduced serum CK (188.60 ± 81.16 vs. 566.75 ± 186.24 U/L) and LDH (179.70 ± 54.47 vs. 463.65 ± 197.58 U/L) levels compared with the LPS group (all p  < 0.05). In LPS-stimulated H9c2 cells, YXTLD dose-dependently enhanced cell viability, suppressed the expression of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α), reduced ROS production and lipid peroxidation, restored antioxidant capacity, and inhibited apoptosis. At 50 μg/mL, YXTLD markedly decreased IL-6, IL-1β, and TNF-α levels by ~78%, 63%, and 92%, respectively (all p < 0.05). ROS and apoptotic cell proportions were progressively reduced with increasing YXTLD concentrations, reaching reductions of ~82% and 95%, respectively, at 150 μg/mL (p < 0.001). Mechanistically, YXTLD activated the Nrf2 signaling pathway by promoting nuclear Nrf2 translocation and upregulating its downstream antioxidant proteins, including heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), and glutamate-cysteine ligase modifier (GCLM). YXTLD also restored CAT and GSH levels while reducing MDA accumulation, indicating attenuation of oxidative stress.

YXTLD protects against sepsis-induced cardiac dysfunction by attenuating inflammation, oxidative stress, and apoptosis through activation of the Nrf2 signaling pathway. These findings provide a pharmacological basis for YXTLD as a potential therapeutic strategy for sepsis-associated cardiac dysfunction.