AIM To unveil the mechanisms by which Shenxian Shengmai Oral Liquid mitigates endoplasmic reticulum stress and ameliorates sinus node fibrosis in sick sinus syndrome (SSS) model in mice via Nrf2/HO-1 signaling pathway so as to provide a theoretical foundation for clinical application of traditional Chinese medicine formulations in the prevention and treatment of SSS.

METHODS Fifty SPF-grade C57B6 mice were selected as experimental subjects and randomly assigned into five groups using a randomized number method: sham operation control group (Sham group), SSS model group (SSS group), and respectively low, medium, and high dosage groups of Shenxian Shengmai Oral Liquid (SXSM-L group, SXSM-M group, SXSM-H group). An SSS mouse model was established using an AngII method with a subcutaneously implanted osmotic pump. Heart rate metrics were collected at various time points (1, 7, 14, 21, 28 days) and pathological changes in the sinoatrial node (SAN) region were observed with HE and Masson staining. ELISA was employed to detect oxidative stress markers, immunofluorescence was used to measure intracellular ROS levels and Western blot was used to assess the expressions of endoplasmic reticulum stress proteins and Nrf2/HO-1 signaling pathway proteins.

RESULTS Shenxian Shengmai Oral Liquid significantly increased heart rate in SSS mice and markedly alleviated sinus node damage and fibrosis (P<0.05). Furthermore, it effectively reduced the serum levels of MDA in SSS mice and promoted the specific expressions of SOD and CAT (P<0.05). Additional studies revealed that Shenxian Shengmai Oral Liquid significantly up-regulated the expressions of SERCA2a, GRP78, HO-1, Nrf2, and Trx-1 proteins in the SAN region of SSS mice and down-regulated the expressions of caspase-12 (P<0.05), with a regulatory effect that was positively correlated with the concentration of the drug (P<0.05).

CONCLUSION Shenxian Shengmai Oral Liquid facilitates the activation of the Nrf2/HO-1 signaling pathway, effectively easing endoplasmic reticulum stress in sinus node cells, preserving the balance of intracellular Ca²⁺ and thus regulating the intrinsic rhythm of sinus node cells and hindering the fibrotic process within the sinus node.